WO2009007661A2 - Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma - Google Patents
Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma Download PDFInfo
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- WO2009007661A2 WO2009007661A2 PCT/FR2008/051251 FR2008051251W WO2009007661A2 WO 2009007661 A2 WO2009007661 A2 WO 2009007661A2 FR 2008051251 W FR2008051251 W FR 2008051251W WO 2009007661 A2 WO2009007661 A2 WO 2009007661A2
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- vwf
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- adamts13
- plasma
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/18—Ion-exchange chromatography
-
- A—HUMAN NECESSITIES
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6489—Metalloendopeptidases (3.4.24)
Definitions
- the present invention relates to the field of protein purification.
- the invention relates to a method for reducing the amount of ADAMTSI 3 present in a von Willebrand factor solution (VWF) and the use of chromatography media and specific buffers for reducing the amount of ADAMTSI 3 present in such samples.
- VWF von Willebrand factor solution
- VWF Von Willebrand factor
- S-S bridges a set of multimers linked by S-S bridges, whose base element has a molecular weight of around 250 kilodaltons (KDa).
- KDa kilodaltons
- the smallest form of VWF in plasma is a dimer of 500 KDa and the largest forms are multimers of this dimer whose molecular weight can reach 20 million daltons.
- This assembly of the subunits into multimers may be specific for the producer cells, the VWF being synthesized and polymerized in the megakaryocytes and in the endothelial cells.
- This factor plays a key role in hemostasis by two distinct functions: as adhesion protein it allows adhesion and aggregation of blood platelets on the vascular subendothelium (and thus participates in the process of primary hemostasis at level of the damaged vessels) and, on the other hand, it ensures the stabilization and transport of Factor VIII (FVIII) in the bloodstream.
- a VWF (quantitative) congenital deficiency or a structural abnormality of this factor (qualitative) leads to von Willebrand disease, which manifests as mucocutaneous haemorrhage. This disease is very heterogeneous in its clinical expression and poses serious problems in case of surgery. Treatment of Willebrand disease is required to correct abnormalities in primary hemostasis (bleeding time) and coagulation (activated partial thromboplastin time and FVIII coagulant activity, FVIII: C).
- the disease is treated by substitution therapy with VWF-enriched human plasma derivatives (eg cryoprecipitated plasma fraction, FVIII concentrates containing sufficient VWF (FVIII / VWF concentrate) or VWF concentrates (lacking FVIII ).
- VWF-enriched human plasma derivatives eg cryoprecipitated plasma fraction, FVIII concentrates containing sufficient VWF (FVIII / VWF concentrate) or VWF concentrates (lacking FVIII ).
- Willebrand disease may or may not be associated with FVIII deficiency depending on whether the protein is absent or qualitatively abnormal, respectively.
- FVIII / VWF concentrate When the patient with VWF expresses normally FVIII it is better to use a VWF concentrate devoid of FVIII.
- the use of such a concentrate makes it possible to compensate for the only VWF deficiency and to avoid excess FVIII.
- Excess FVIII can lead to serious complications such as venous thrombosis or pulmonary embolism.
- VWF concentrates are generally very unstable in solution if the VWF is denatured by proteolytic enzymes such as I ⁇ DAMTS13.
- L ⁇ DAMTS13 is a protease of the family of metal loproteases that is naturally present in human plasma. Its role is to convert VWF's long hyper-active multimers into smaller, less active multimers.
- ADAMTS 13 is able to denature VWF in vivo but also in vitro, for example in solutions derived from plasma containing VWF, such as VWF concentrates or FVIII / VWF concentrates. Although these plasma derivatives can generally be stored as a freeze-dried powder for several years, the presence of ADAMTS13 affects the stability of VWF when the freeze-dried powder is dissolved. This VWF stability problem precludes certain forms of therapeutic treatment, for example continuous or discontinuous infusion therapy for several days.
- This mode of treatment allows the maintenance of constant circulating levels of VWF to avoid the occurrence of rates outside the therapeutic areas when the administration is performed by discontinuous injection.
- the Applicant has therefore sought to develop efficient means for reducing the amount of ADAMTS13 protein present in compositions derived from the plasma containing VWF, in order to increase their properties of stability over time.
- the subject of the invention is the use of an ion exchange chromatography medium comprising a large-pore vinyl polymer resin carrying DEAE groups and a buffer comprising trisodium citrate.
- sodium chloride, calcium chloride, glycine and lysine to reduce the amount of ADAMTS13 present in a solution derived from plasma containing human VWF and ADAMTS13.
- the invention also relates to a method for reducing the amount of ADAMTS13 present in a solution derived from plasma containing human VWF comprising an ion exchange chromatography step on a large-pore vinyl polymer type resin bearing DEAE groups made in a buffer comprising trisodium citrate, sodium chloride, calcium chloride, glycine and lysine
- Figure 1 illustrates a study of the stability of the RCo activity of the VWF concentrate.
- Figure 1 shows a graph showing the concentration according to VWF time: RCo of a VWF concentrate lacking ADAMTS13 stored in cassettes or syringes.
- FIG. 2 illustrates a study of the VWF antigen stability of the VWFLa concentrate.
- FIG. 2 represents a graph showing the concentration as a function of time of the VWF: Ag of a VWF concentrate containing no ADAMTS13 stored in cassettes or cassettes. syringes.
- the present invention relates to the use of an ion exchange chromatography medium comprising a large-pore vinyl polymer type resin bearing DEAE (diethylaminoethyl) groups and a buffer comprising trisodium citrate, sodium, calcium chloride, glycine and lysine to reduce the amount of ADAMTS13 present in a solution derived from plasma containing human VWF.
- DEAE diethylaminoethyl
- the present invention also relates to a method for reducing the amount of ADAMTS13 present in a solution derived from plasma containing human VWF comprising an ion exchange chromatography step on a large-pore vinyl polymer type resin bearing DEAE moieties. made in a buffer comprising trisodium citrate, sodium chloride, calcium chloride, glycine and lysine.
- the ion exchange chromatography support is a DEAE-Fractogel® TSK 650 resin (also called DEAE-Toyopearl 650) equilibrated with equilibration buffer comprising 0.01 M trisodium citrate, sodium chloride 0.1 M, 0.001 M calcium chloride, 0.12 M glycine and 0.016 M lysine at pH 7 ⁇ 0.1.
- DEAE-Fractogel® TSK 650 is a hydrophilic synthetic gel.
- the support is a copolymer of oligoethylene glycol, glycidinemethacrylate and pentaerythritol dimethacrylate on which are grafted DEAE groups such as -O-CH 2 -CH 2 N + (C 2 H 5 ) 2 HCl, which constitutes an anion exchanger weakly alkaline.
- DEAE-Fractogel® TSK 650 is available in two particle sizes (after rehydration): Type S (0.025-0.050 mm) and Type M (0.045-0.090 mm); both types can be used for the present invention.
- the plasma-derived solutions include blood plasma derivatives, such as the cryoprecipitate fraction (unpurified fraction) and derivatives thereof. purified cryoprecipitate.
- the present invention particularly relates to plasma-derived solutions that may contain VWF.
- the cryoprecipitated fraction of the plasma, prepurified, optionally having undergone viral inactivation treatment is applied to the balanced ion exchange chromatography column.
- the fraction retained is then eluted by increasing the concentration of sodium chloride in the 0.14-0.15M buffer.
- This step makes it possible to reduce the amount of ADAMTS13 by more than 500 times compared to the amount of ADAMTS13 initially contained in the starting plasma sample (Table 1).
- the quantity of ADAMTS13 present in a solution derived from the plasma containing von Willebrand factor is reduced by carrying out two successive stages of ion exchange chromatography, under the conditions described above, in particular with the balancing buffer described above.
- the fraction eluted after the use of the first column can be applied again to a second chromatography column identical to the first one, under the same conditions as on the first, except that after elimination of the filtrate and rinsing of the column with the equilibration buffer, the proteins adsorbed on the chromatographic support are eluted by increasing the concentration of sodium chloride of the buffer at 0.15-0.17 M.
- This additional chromatography allows to reduce the amount of ADAMST13 by more than 2000-fold compared to the amount of ADAMTS13 contained in the starting plasma sample (Table 1).
- the reduction of the amount of ADAMTS13 is greater than 200 times, 300 times, 400 times, 500 times, 600 times, preferably greater than 700 times, 800 times, 900 times, 1000 times, 1500 times, 2000 2500 times compared to the amount of ADAMTS13 contained in the starting plasma sample.
- the fraction eluted from the ion exchange chromatography support, or the ion exchange chromatography medium used secondly, according to the embodiment of the invention can then be subjected to a gelatin-Sepharose support affinity chromatography step, in the presence of a balancing buffer identical to the equilibration buffer used for carrying out the step or steps (s). ) of ion exchange chromatography.
- the gelatin-Sepharose chromatography support has the ability to retain contaminating residual fibronectin molecules.
- the choice of the gel carrier tuple associated with the gelatin is not an essential characteristic for carrying out this subsequent chromatography step.
- a support for affinity chromatography it is also possible to use a support chosen from gelatin-Ultrogel®, gelatin-Spherodex® and gelatin-Fractogel®.
- a gelatin-sepharose® carrier is preferably used. In vitro tests confirmed the stability of the concentrate containing VWF thus obtained when it is dissolved (Example 3).
- compositions derived from plasma are obtained from compositions having a reduced content of ADAMTS13 protein and which are enriched in VWF.
- Such compositions because of the time-stability properties of VWF, can be used in liquid form to perform medical treatments by administering VWF intravenously.
- the subject of the present invention is also the use of a liquid composition with reduced content of ADAMTS13 protein and enriched with VWF, as obtained by the method defined in the present description, for the manufacture of a medicament intended to prevent or prevent to treat a pathology related to a biologically active VWF deficiency.
- said medicament is in a form adapted to its intravenous administration.
- said drug is in a lyophilized form, to which the appropriate amount of sterile and pyrogen-free water is added to provide a liquid composition suitable for intravenous administration.
- said drug is in a liquid form that can be used directly for intravenous administration.
- the present invention also relates to a method for preventing or treating a disease related to a biologically active VWF deficiency, characterized in that it comprises a step in which a composition enriched with VWF is administered to a patient who requires it. and depleted of ADAMTS13 protein, as obtained according to the method defined in the present description.
- the step of administering the composition consists of an intravenous administration step.
- the intravenous administration step consists of a continuous infusion step, that is to say a continuous infusion stage for a duration of at least 8 hours and up to 200 hours. the duration of this step being adapted to the state of the patient.
- the continuous infusion administration step generally has a duration of from 8 hours to 120 hours, and usually up to 24 hours.
- the step of administration by continuous infusion is carried out with a single container or bottle of a composition enriched in VWF and depleted in ADAMTS13 obtained according to the method of the invention.
- a single container containing a single batch of the composition during the entire duration of the continuous infusion administration step is made possible due to the high stability of the VWF in the composition.
- Therapeutic methods comprising a step of administering a composition enriched with von Willebrand factor are, in themselves, known in the state of the art. Such methods have been described for example by Marti nowitz et al.
- the composition enriched in VWF and depleted in protein ADAMTS13 is administered to the patient, by continuous infusion, so as to administer to said patient an amount of von Willebrand factor ranging from 20 to 200 VWF: RCo IU / kg, / 24 h.
- the compositions used, obtained directly or indirectly by the process of the invention advantageously have a VWF content ranging from 10 to 250 IU / ml, for example 100 IU / ml.
- Plasma Blood was collected in the presence of sodium citrate (4%) or CPD anticoagulant solution (citrate, phosphate, dextrose) and frozen no later than 6 hours after collection. Plasma was obtained after centrifugation, and frozen at -60 ° C and stored at -35 ° C. The batches of plasma contain from 1800 to 2000 liters and are collected in batches of 4000 liters for each implementation of the process. For thawing, the plasma was placed in a chamber at -7 ° C for at least 12 hours to ensure a slow and steady warming and then thawed in a thermostatically controlled chamber at 0-2 ° C with constant stirring. Cryoprecipitate (which represents approximately 9 g / l of plasma) was recovered by cold centrifugation.
- Cryoprecipitate which represents approximately 9 g / l of plasma
- cryoprecipitate was redissolved and adsorbed on aluminum hydroxide to remove the main contaminants, i.e. components of the prothrombin complex (particularly Factor VII), Factor XII.
- the supernatant was then cooled to 15 ° C (which partly eliminates fibrinogen and fibronectin). -Validation inactivation treatment.
- the solution containing FVIII-VWF was subjected to a solvent-detergent treatment known for its effectiveness against lipid-enveloped viruses (Horowitz et al., 1985, Transfusion, 25, 516-522.) And which comprises an incubation of 8 hours at 25 ° C. in the presence of 0.3% th-n-butyl phosphate (TnBP) and 1% Tween 80. Chromatographic separation method. The first chromatography was carried out on a DEAE-Fractogel (M) TSK 650 (Merk) column.
- the equilibration buffer contains trisodium citrate (0.01 M), calcium chloride (0.001 M), sodium chloride (0.1 M), glycine (0.12 M) and L -lysine (0.016M). VWF, FVIII and fibronectin are retained by the column; the contaminating proteins (mainly fibrinogen and IgG) weakly or not fixed by the column and the residues of the viral inactivation treatment are removed by several successive washings with the same buffer.
- the column was used with a linear flow rate of 100 cm / hour.
- the column adsorbed fraction, containing VWF, is eluted by an increase in the NaCl concentration of the 0.15M buffer.
- the fraction containing the VWF eluted from this first column is reinjected into a second column, identical to the first and under the same conditions, after a slight dilution with the equilibration buffer, to adjust the ionic strength of the VWF fraction to the equivalent of 0.1 M sodium chloride.
- the VWF-containing column-adsorbed fraction is eluted by an increase in the NaCl concentration of the 0.15 M buffer.
- This second eluate is subjected to a third purification step on a column of gelatin-Sepharose CL4B (Pharmacia) equilibrated with the elution buffer of the previous column, to eliminate fibronectin.
- This affinity chromatography gel has a fibronectin retention capacity of> 5 mg / ml which makes it possible to reduce this contaminant to undetectable quantities ( ⁇ 4 mg / l) in the fraction.
- the VWF concentrate lacking ADAMTS13 is found in the filtrate of this last stage and can be directly conditioned and lyophilized.
- the final concentrate obtained requires no addition of stabilizer.
- the purpose of this example is to measure the reduction factor of ADAMTS13 present in a VWF concentrate made according to Example 1.
- starting plasma B cryoprecipitate between the solvent / detergent and the first DEAE
- C eluate of the first DEAE chromatography
- the ADAMTS concentration of each sample was measured with an IMUBIND® ADAMTS13 ELISA Kit (American Diagnostica) using rabbit anti-human ADAMTS13 antibodies.
- the ADAMTS13 reduction factor is calculated by dividing the ADAMTS / VWF: RCo value of the fraction by the ADAMTS / VWF: RCo value for the plasma fraction.
- the reduction factor of ADAMTS13 after the first chromatography is greater than 700. This reduction factor is of the order of 2500 after the second chromatography. By cons the third chromatography does not reduce the amount of ADAMTS13. This example shows the high efficiency of the chromatography columns and buffers used for the removal of ADAMTS13.
- the objective of this example is to evaluate the biological stability after reconstitution of the freeze-dried VWF concentrate free of ADAMTS13 manufactured according to Example 1 in different containers and in a state of common practice during fractionation of doses in syringe or batch or when administering the product as a continuous infusion using an infusion pump.
- VWF RCo 1010 Ul / 10 ml bottle
- VWF RCo: 1000 IU / 10 ml bottle
- BCS automaton (Dade Behring, Marburg GmbH) for the assays of the ristocetin co-factor activity (VWF: Rco) and the Willebrand Antigen assays (VWF: Ag).
- VWF Willebrand Antigen Assay
- VWF reagent Ag Dade Behring (Dade Behring Marburg GmbH) containing: - 1 vial
- VWF Ag diluent for latex reagent 4ml: solution containing glycine, for the dilution of the reagent Latex
- the freeze-dried concentrate of VWF lacking ADAMTS13 is a powder to be reconstituted extemporaneously with water for injections.
- Syringes at TO, the products were reconstituted with the supplied solvent (water for injection) and the equipment (transfer system equipped with a sterilizing filter vent and a filter needle), then transferred to syringes in a fume hood. laminar airflow (Class A), in a controlled atmosphere room (Class C). The study was performed in static conditions for 3 days (72h), the preparations were stored at room temperature and protected from light.
- VEQ A, VEQ B and the standard plasma were reconstituted with 1 ml of non-cold distilled water and then allowed to stabilize for 1 hour.
- assay of the VWF RCo activity
- a standard range was carried out the same day as the assays. Calibration was performed by dilution of the standard with buffer
- VEQ A and VEQ B controls validated the calibration.
- the controls were ironed at the end of the passage of the samples corresponding to the syringes, then before those corresponding to the cassettes, thus validating a new reconstitution of the platelet reagent.
- the standard range was validated by the passage of the VEQ A and VEQ B controls.
- the VWF present in the sample causes, in the presence of the ristocetin (antibiotic), an agglutination of the stabilized platelets contained in the reagent BC von Willebrand reagent.
- the agglutination process decreases the turbidity of the reaction mixture.
- the coagulation device (Dade Behring BCS automaton) measures the change in Optical Density and automatically calculates the cofactor activity of the sample ristocetin in% of normal. We achieved a range of 6 points from standard plasma of 10 to 150% (10, 20, 40, 60, 100 and 150%).
- VWF reactive BC contains stabilized platelets, ristocetin and EDTA, in freeze-dried form. After reconstitution with 4 ml of distilled water, the reactive BC von Willebrand reagent is allowed to stabilize for 15 minutes without stirring. It is then shaken twice 5 sec vortex very gently, then is placed on the BCS. This must be stirred every 30 min. The NaCl used to dilute the samples is also placed on the BCS.
- Von Willebrand causes the agglutination of small polystyrene particles coated with specific antibodies (rabbit Ac), fixed not covalent bond.
- This agglutination is measured by turbidimetry on the BCS. Turbidimetry is directly proportional to the level of VWF Ag present in the sample. A 5-point range was made from standard plasma of 10% to 180% (10, 40, 70, 150 and 180%).
- Sample Preparation Samples were diluted 1: 10 in sample dilution buffer + bromophenol blue to adjust the VWF: Ag level to about 0.1 IU / ml. The samples were then heated for 30 minutes at 60 ° C.
- Electrophoresis 30 ⁇ L of samples were deposited in the wells of the agarose gel. As soon as the electrophoresis was stopped, the gel was immersed in a beaker of water distilled and rinsed for at least 1 hour with gentle agitation. The gel was then dried under a stream of cold air and then saturated for 1 hour in the saturation buffer. The gel was incubated overnight with gentle shaking in a bath of polyclonal anti-VWF antibodies bound to alkaline phosphatase (anti-VWF-PA) diluted in 50 mM TBS buffer. After incubation, the gel was incubated, with stirring, with several successive baths of wash buffer, for at least 2 hours. The revealing solution was prepared by adding to 100 ml of 0.1 M Tris pH 9.5, 1 ml of solution A + 1 ml of solution B (solutions of the kit).
- FIGS. 1 and 2 Stabilities as a function of time according to co-factor activity of ristocetin and von Willebrand antigens are shown in FIGS. 1 and 2.
- Table 2 Syringe Dosage Results (Raw, Mean, and Standard Deviation)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0813742-0A2A BRPI0813742A2 (pt) | 2007-07-05 | 2008-07-04 | Utilização de um suporte de cromatografia de trocas de íons e processo para reduzir a quantidade de adamts13 presente em uma solução derivada do plasma |
CA002691604A CA2691604A1 (fr) | 2007-07-05 | 2008-07-04 | Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma |
AU2008273988A AU2008273988A1 (en) | 2007-07-05 | 2008-07-04 | Use of a chromatography substrate for reducing the amount of ADAMTS13 in a solution derived from plasma |
CN2008800234967A CN101918546A (zh) | 2007-07-05 | 2008-07-04 | 层析基质减少来自血浆的溶液中adamts13的量的用途 |
EP08806168A EP2167657A2 (fr) | 2007-07-05 | 2008-07-04 | Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma |
JP2010514085A JP2010532337A (ja) | 2007-07-05 | 2008-07-04 | 血漿からの溶液中のadamts13の量を減少させるためのクロマトグラフィ担体の使用 |
US12/667,751 US8025803B2 (en) | 2007-07-05 | 2008-07-07 | Use of a chromatography substrate for reducing the amount of ADAMTS13 in a solution derived from plasma |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0756303 | 2007-07-05 | ||
FR0756303A FR2918375B1 (fr) | 2007-07-05 | 2007-07-05 | Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma |
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WO2009007661A2 true WO2009007661A2 (fr) | 2009-01-15 |
WO2009007661A3 WO2009007661A3 (fr) | 2009-02-05 |
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PCT/FR2008/051251 WO2009007661A2 (fr) | 2007-07-05 | 2008-07-04 | Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma |
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Country | Link |
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US (1) | US8025803B2 (fr) |
EP (1) | EP2167657A2 (fr) |
JP (1) | JP2010532337A (fr) |
KR (1) | KR20100041731A (fr) |
CN (1) | CN101918546A (fr) |
AU (1) | AU2008273988A1 (fr) |
BR (1) | BRPI0813742A2 (fr) |
CA (1) | CA2691604A1 (fr) |
FR (1) | FR2918375B1 (fr) |
WO (1) | WO2009007661A2 (fr) |
Families Citing this family (3)
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FR2918375B1 (fr) * | 2007-07-05 | 2009-10-16 | Lab Francais Du Fractionnement | Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma |
FR2933496B1 (fr) * | 2008-07-02 | 2012-10-05 | Lfb Biotechnologies | Procede de mesure du taux de facteur vii active dans un echantillon |
US8945895B2 (en) * | 2009-07-31 | 2015-02-03 | Baxter International Inc. | Methods of purifying recombinant ADAMTS13 and other proteins and compositions thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002042441A2 (fr) * | 2000-11-22 | 2002-05-30 | Baxter Aktiengesellschaft | Polypeptide de la protease de clivage du facteur de von willebrand (vwf), acide nucleique codant ce polypeptide et utilisation de ce polypeptide |
EP1391516A1 (fr) * | 2001-04-25 | 2004-02-25 | Juridical Foundation, The Chemo-Sero-Therapeutic Research Institute | Enzyme de clivage du facteur de von willebrand (vwf) |
WO2006133955A1 (fr) * | 2005-06-17 | 2006-12-21 | Baxter International Inc. | Compositions contenant adamts13, presentant une activite thrombolytique |
Family Cites Families (5)
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US4753983A (en) * | 1986-05-07 | 1988-06-28 | Bioprobe International, Inc. | Polymeric matrix for affinity chromatography and immobilization of ligands |
WO2003016492A2 (fr) * | 2001-08-16 | 2003-02-27 | The Regents Of The University Of Michigan | Genes, proteines et variants adamts13, et utilisations de ceux-ci |
EP1852442B1 (fr) * | 2005-02-14 | 2012-03-14 | Alfresa Pharma Corporation | Anticorps pour le dosage de l'activite adamts13 et procede de dosage de l'activite |
FR2918375B1 (fr) * | 2007-07-05 | 2009-10-16 | Lab Francais Du Fractionnement | Utilisation d'un support de chromatographie pour reduire la quantite d'adamts13 dans une solution derivee du plasma |
US8945895B2 (en) * | 2009-07-31 | 2015-02-03 | Baxter International Inc. | Methods of purifying recombinant ADAMTS13 and other proteins and compositions thereof |
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2007
- 2007-07-05 FR FR0756303A patent/FR2918375B1/fr not_active Expired - Fee Related
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2008
- 2008-07-04 AU AU2008273988A patent/AU2008273988A1/en not_active Abandoned
- 2008-07-04 CN CN2008800234967A patent/CN101918546A/zh active Pending
- 2008-07-04 EP EP08806168A patent/EP2167657A2/fr not_active Withdrawn
- 2008-07-04 CA CA002691604A patent/CA2691604A1/fr not_active Abandoned
- 2008-07-04 JP JP2010514085A patent/JP2010532337A/ja not_active Withdrawn
- 2008-07-04 KR KR1020107000053A patent/KR20100041731A/ko not_active Application Discontinuation
- 2008-07-04 WO PCT/FR2008/051251 patent/WO2009007661A2/fr active Application Filing
- 2008-07-04 BR BRPI0813742-0A2A patent/BRPI0813742A2/pt not_active IP Right Cessation
- 2008-07-07 US US12/667,751 patent/US8025803B2/en not_active Expired - Fee Related
Patent Citations (3)
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WO2002042441A2 (fr) * | 2000-11-22 | 2002-05-30 | Baxter Aktiengesellschaft | Polypeptide de la protease de clivage du facteur de von willebrand (vwf), acide nucleique codant ce polypeptide et utilisation de ce polypeptide |
EP1391516A1 (fr) * | 2001-04-25 | 2004-02-25 | Juridical Foundation, The Chemo-Sero-Therapeutic Research Institute | Enzyme de clivage du facteur de von willebrand (vwf) |
WO2006133955A1 (fr) * | 2005-06-17 | 2006-12-21 | Baxter International Inc. | Compositions contenant adamts13, presentant une activite thrombolytique |
Non-Patent Citations (2)
Title |
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WO2009007661A3 (fr) | 2009-02-05 |
US20100193440A1 (en) | 2010-08-05 |
JP2010532337A (ja) | 2010-10-07 |
FR2918375B1 (fr) | 2009-10-16 |
CN101918546A (zh) | 2010-12-15 |
BRPI0813742A2 (pt) | 2014-12-30 |
FR2918375A1 (fr) | 2009-01-09 |
KR20100041731A (ko) | 2010-04-22 |
CA2691604A1 (fr) | 2009-01-15 |
EP2167657A2 (fr) | 2010-03-31 |
US8025803B2 (en) | 2011-09-27 |
AU2008273988A1 (en) | 2009-01-15 |
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