WO2012080422A1 - Procédé de séparation, de concentration ou de purification d'une protéine de plasma (sanguin) ou d'un constituant viral d'un mélange - Google Patents

Procédé de séparation, de concentration ou de purification d'une protéine de plasma (sanguin) ou d'un constituant viral d'un mélange Download PDF

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Publication number
WO2012080422A1
WO2012080422A1 PCT/EP2011/072967 EP2011072967W WO2012080422A1 WO 2012080422 A1 WO2012080422 A1 WO 2012080422A1 EP 2011072967 W EP2011072967 W EP 2011072967W WO 2012080422 A1 WO2012080422 A1 WO 2012080422A1
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Prior art keywords
blood
sorbent
liquid
plasma protein
range
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PCT/EP2011/072967
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German (de)
English (en)
Inventor
Dirk MÜLLER
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Previpharma Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/01—DNA viruses
    • 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
    • C07K1/20—Partition-, reverse-phase or hydrophobic interaction chromatography
    • 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
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation

Definitions

  • the present invention relates to a method for separating, concentrating or purifying a (blood) plasma protein or viral component from a mixture containing this (blood) plasma protein or viral component from a mixture using sorbents whose surface is functionalized with at least two receptor molecules wherein the sorbents are used as chromatography material and wherein the method involves virus inactivation.
  • the solvent-detergent method has been used successfully for many years. This method is based on the fact that many viruses, such as HIV or hepatitis B, have a lipid envelope that can be destroyed by the addition of a "soap".
  • the soap consists for the most common method from a mixture of organic phosphate triester, especially tri-N-butyl phosphate and a nonionic soap such as p-tert-(octylphenoxy) polyethoxy ethanol (Triton ® X-100). By treatment with these two reagents all viruses can be inactivated, which have a lipid envelope.
  • the reagents can be removed mechanically and chromatographically to obtain virus-free plasmas suitable for transfusion.
  • the mechanical removal especially of the organic phosphate is achieved by extraction by means of an oil, while the nonionic soap can be separated by means of reversed-phase silica gel or ion exchange resin.
  • Methods for carrying out solvent-detergent processes are described, for example, by P. Horowitz et al., Blood, 79, 826-831 (1992) or M. Pourmokhtar, DARU J. Pharm. Volume 11, no. 2 (2003).
  • CA 1 201 063 describes the preparation of IgG which is suitable for intravenous administration, wherein a plasma fraction is subjected to a two-stage separation process with two different anion exchange phases. At each stage, the buffer used to equilibrate the anion exchange resin is also used to elute the IgG-containing fraction from the resin. From US 4,983,722 the use of anion exchange chromatography for the purification of antibody preparations is known. In this method, a solution containing antibody and contaminating protein A is contacted with an anion exchange resin, the antibodies being eluted from the resin under conditions of increasing ionic strength.
  • DE 698 23 931 describes a method which combines a viral inactivation with a purification and separation of gamma globulins, and with which these gamma globulins can be obtained in a purity of greater than 99%.
  • viral inactivation is achieved by treatment with caprylic acid at a pH of between 3.8 and 4.9.
  • the caprylic acid used acts analogously to an organic phosphate / nonionic soap mixture which attacks the lipid envelope of viruses.
  • the process described in DE 698 23 931 is based on the purification of Gamma globulins by means of ion exchange chromatography, wherein a strong anion exchanger and then a weak anion exchanger for cleaning are used. In the purification of Cohn II + III fractions, this process achieves a total yield of 69% of the paste, which is significantly increased compared to the washing process with alcohol (yield 48%).
  • the technical problem addressed by the present invention is therefore to provide a novel separation, concentration and / or purification method for (blood) plasma proteins or viral components involving virus inactivation without the drawbacks of the previously known method indicated in the preceding section must be accepted.
  • This means that the method allows the isolation of the desired (blood) plasma proteins or viral components in high purity and at the same time inactivating existing viruses and a high yield is to be achieved.
  • the functional integrity of the (blood) plasma proteins or viral components should not be impaired and the use of expensive materials should be kept to a minimum.
  • the new process should allow the use of standard cleaning and sterilization protocols of the equipment during use, thus ensuring the approval of the process for the manufacture of pharmaceutical products by the relevant authorities.
  • the object of the present invention is to provide the desired (blood) plasma proteins or viral components in an economically favorable manner and in a quality suitable for pharmaceutical products.
  • This technical problem is solved by a method for separating, concentrating and / or purifying a (blood) plasma protein or viral component from a mixture containing this (blood) plasma protein or viral component, the mixture containing the (blood) plasma protein or the viral component natural human or animal blood, or an intermediate or finished product of natural human or animal blood, in particular blood plasma or proteinaceous precipitate obtained from a blood plasma fractionation process
  • step (iv) filtering the mixture obtained from step (iii) via a sorbent 2, wherein the sorbents 1 and 2 are solid support materials whose surfaces are each functionalized with at least two receptor molecules, the surface of the sorbent 1 with pyridine-4-carboxyamido Residues and 3-carboxymidopropionic acid residues and the surface of sorbent 2 is functionalized with benzopyrrole residues and 3-azapyrrole residues.
  • the method described above can be advantageously developed further in that, following the binding of the (blood) plasma protein or the viral component to the sorbent 1 in step (i), the sorbent is washed with a further ability.
  • the method described above can be improved by washing and / or regenerating the sorbent with another liquid following dissolution of the (blood) plasma protein or viral component from the sorbent 1 in step (ii).
  • the method can also be developed in such a way that, before the binding of the (blood) plasma protein or viral component to the sorbent in the Step (i) and / or (iv) the sorbent is equilibrated with another liquid.
  • the (blood) plasma proteins or viral components are preferably antibodies, and more preferably immunoglobulins. Of these, especially IgG, IgA and IgM are particularly interesting for the method described. In addition to antibodies, fragments or compounds of natural antibodies, genetically engineered variants of viral components can be effectively purified by the described method.
  • the mixture containing the (blood) plasma protein or the viral component may be a natural or synthetic mixture, in particular the mixture may consist of blood plasma or an intermediate or end product of blood plasma.
  • the method is performed using blood plasma or a proteinaceous precipitate obtained by a blood plasma fractionation method.
  • Cohn precipitates are commercially available as A + 1, II + III or I + II + III pastes.
  • the blood is of natural human or animal origin, however the use of human blood is preferred.
  • the sorbents 1 and 2 used in the process are each a solid support material whose surface is functionalized with at least two receptor molecules.
  • the support material particularly preferably consists of a porous base material which is initially coated with this amine compound for incorporation and crosslinking of a polyamine compound and is subsequently functionalized with the formation of covalent bonds between the receptor molecules and the polyamine with the attachment of functionalized receptor molecules.
  • the porous base material is suitably a porous polystyrene.
  • the polyamine compound the use of polyvinylamine has been found to be particularly useful.
  • the carrier material is made by adding a crosslinking agent, such as diepoxide, crosslinked.
  • the preparation of support materials which are coated with polyvinylamine has already been described in the prior art, for example in EP 1 141 038 and EP 1 232 018.
  • the resulting polyamine-coated sorbent is functionalized with two organic radicals.
  • the use of acid-functionalized receptor molecules or derivatives thereof in which amide linkages are formed after reaction with the polyvinylamine has proven to be particularly useful.
  • receptor molecules can be substituted by a pyridine ring (-C 5 H 4 N) whose hydrogen atoms and carboxyl groups (-COOH) lead to particularly selective sorbents. Both the pyridine ring and the carboxyl group can be connected via a covalently bound linker with the polyamine material.
  • the pyrrole radical may in particular be a 3-azapyrrole radical and particularly preferably a 4-imidazolacryliamide radical.
  • the benzopyrrole residue is preferably a 3-indolpropionamide residue, with the combination of said specific residues having been found to be particularly effective.
  • the benzene-pyrrole and pyrrole radicals can also be linked to the polyamine compound in the solid support material via a linker, as described above for the sorbent 1.
  • the method can be further advantageously characterized in that the liquids 1 in step (i) is a buffer.
  • the buffer preferably has a concentration in the range of 1 to 100 mM, especially 2 to 20 mM. Irrespective of the concentration, the pH of the liquid is expediently close to the isoelectric point p1 of the bound protein or peptide, in particular in a pH range of about 4.0 to 6.0.
  • ratio of the (blood) plasma protein or viral component in the mixture to the volume of the sorbent there are no particular limitations on the ratio of the (blood) plasma protein or viral component in the mixture to the volume of the sorbent. However, it has proven to be expedient to choose a ratio of 2-20, in particular 8-16 mg / ml.
  • the ratio of liquid 1 to the mixture containing the protein or peptide in step (i) is also not particularly limited. For this, a ratio range of 5: 1 to 15: 1, in particular 8: 1 to 10: 1 based on the weight of liquid to protein has been found to be particularly suitable.
  • the buffer used as liquid 1 in step (i) is preferably a substance which has a pKa value in the range from 4.0 to 6.0, since this ensures the highest possible buffer capacity.
  • the buffer of the liquid 1 of carbonic acid / silicate buffers, acetic acid buffers, citrate Buffers, phosphate buffers and / or 2- (N-morpholino) ethanesulfonic acid (MES) buffers selected.
  • the liquid 2 used in step (ii) may also be a buffer having a higher concentration than the buffer used in step (i), in particular a concentration in the range of 50-200 mM and preferably 80-120 mM.
  • the pH of the liquid 2 is suitably in the region of the isoelectric point p1 of the protein or peptide, or in the range of 6.5-8.5.
  • the isoelectric point of the protein or peptide is within this range.
  • Buffers are also used whose pKa is within this pH interval, such as carbonate buffer, ammonia buffer, TRIS buffer, HEPES, HEPPS or phosphate buffer.
  • the method provides excellent separation lines when the pH of the liquid 1 is in the range of 4.0 to 6.0 and the pH of the liquid 2 is in the range of 6.5 to 8.5.
  • the process can be further advantageously characterized in that the mixture obtained in step (ii) is concentrated before the solvent-detergent process in step (iii). This concentration may conveniently be carried out by ultrafiltration. Furthermore, the liquid 2 should be exchanged with the liquid 3 before carrying out the solvent-detergent process, which can be carried out in an efficient and cost-effective manner, in particular by means of diafiltration.
  • the solvent-detergent process is usually carried out with the addition of a nonionic soap and an organic phosphate, wherein as organic phosphate appropriately tri-N-butyl phosphate is selected, as nonionic soap, however, a p-tert-octylphenol derivative with a Polyethylenglycolrisekette (available for For example under the trade name Triton ® -X-100), or a Polyo- xyethylensorbitanmonooleat monolaurate or in the form of polysorbate 20 and polysorbate 80 (available for example under the trade names Tween ® 20 and Tween ® 80).
  • the respective soap is used in concentrations in the range of 0.2 to 5%, in particular 0.5 to 2%, while for the organophosphate a Concentration of preferably 0.01 to 5%, particularly preferably 0.1 to 0.5%, is selected.
  • viruses present are preferably inactivated by treatment for a period of 4 to 16 hours.
  • the mixture obtained from the solvent-detergent process can be used directly without removal of the reagents by extraction with an oil.
  • the liquid 3 used in step (iv) is preferably also a water-based liquid, in particular a buffer.
  • This expediently has a pH in the range from 3.0 to 6.5.
  • the buffer should further have a concentration (of the buffer) in the range of 50 to 400 mM, especially 150 to 250 mM.
  • the buffer used as liquid 3 is expediently based on an acid whose pKa is in the range of the preferred pH of the buffer, ie in the range from 3.0 to 6.5.
  • acetic acid, citrate, phosphate and / or 2- (N-morpholino) ethanesulfonic acid (MES) can be selected as the buffer base.
  • a buffer is preferably used which has a higher concentration than the liquids 1 and / or 3.
  • the buffer it has proven to be expedient for the buffer to have a concentration in the range from 250 to 3000 mM.
  • a buffer from the same acid / salt system, as it is used as liquid 1 and having the same pH as the liquid used thereafter 1.
  • the sorbent 1 before the application of the mixture in Step (i) are additionally rinsed with the liquid 1.
  • step (iv) as the liquid used for equilibration, it is preferable to use an acid solution, especially acetic acid solution. This should have a concentration in the range of 200 to 600 mM.
  • step (iv) the sorbent 2 is rinsed with the liquid 3 to adjust the pH of the sorbent to the liquid 3 used to apply the mixtures obtained from the solvent-detergent process.
  • step (i) the liquid used in step (i) is expediently used.
  • Both sorbents 1 and 2 can be regenerated by rinsing with strongly basic solution and cleaned of remaining on the sorbents residual protein or viral components.
  • the pH of the basic solution is advantageously at least 9, more preferably a pH of about 10 is used. Any commercially available base may be used as the base, but for reasons of cost it is advisable to use sodium or potassium hydroxide.
  • the sorbent Before the regeneration, in particular of the sorbent 2, the sorbent can additionally be rinsed with an acid solution, in particular with a concentration of between 250 and 1000 mM.
  • the sorbent 2 For the separation of the components present in the mixture of organic phosphate and ionic soap, the sorbent 2 with a high loading of up to 100 mg / ml to isolated (blood) plasma protein or virus component, preferably in the range of 25 to 75 mg / ml, be loaded.
  • the reagents added in the solvent-detergent process can be washed from the column by treatment with 70% isopropanol in water or 70% ethanol in water ,
  • (blood) plasma proteins and viral components in particular immunoglobulins, such as IgG, IgM and IgA, can be purified inexpensively in a few steps, whereby viruses present in the starting material can be effectively inactivated.
  • immunoglobulins such as IgG, IgM and IgA
  • the sorbent 1 is rinsed with 500 mM citrate buffer (pH 5.0) and then equilibrated with the same amount of 10 mM citrate buffer (pH 5.0). Subsequently, a commercial A + 1 paste as a 10% solution in 10 mM citrate buffer at pH 5 is applied to the sorbent and rinsed with the same buffer. In the fractions obtained first, albumin and transferrin (yield quantitative, purity about 90%) are obtained, which can be purified in further purification stages (ion exchangers). After collecting the albumin / transferin fractions, the column was rinsed with additional 10mM citrate buffer at pH (5.0).
  • IgG pre-purified IgG was eluted from the acid by rinsing with 100 mM phosphate buffer at pH 7.4.
  • the IgG thus obtained had a purity of> 80% and was obtained in a yield of> 98%.
  • the product was free of albumin and transferrin.
  • the intermediate obtained was first concentrated by ultrafiltration to about 50 mg / ml IgG. Thereafter, the phosphate buffer was exchanged by diafiltration with an acetate buffer having a concentration of 200 mM and a pH of 4.3 to 4.5. Subsequently, the mixture was subjected to a solvent-detergent treatment by mixing 1% Triton X-100 and 0.3% tri-N-butyl phosphate and allowing it to stand for 8 to 16 hours. Prior to applying this intermediate to sorbent 2, the sorbent was also first equilibrated by rinsing with 400 mM acetic acid solution followed by rinsing with 200 mM acetate buffer at pH 4.3 to 4.5.
  • the intermediate dissolved in acetate buffer was applied to the sorbent with a loading in the range of between 25 and 75 mg / ml of product / sorbent volume.
  • Pure IgG was eluted from the column by rinsing with 200 mM acetate buffer at pH 4.3 to 4.5.
  • the sorbent was rinsed with 500 mM acetic acid and IgA and IgM were recovered with a yield of> 90% in high purity.
  • the IgG thus obtained as a solution with a content of 5% has the following properties: Purity:> 99.5%
  • IgG activity 95-105%
  • IgA 10 - 30 mg / ml ( ⁇ 0.01%)
  • Albonine 50-100 ⁇ g / ml ( ⁇ 0.05%)
  • Residual proteins fibrinogen, haptoglobin, 2-macrogloboline, apolipoprotein A and B and IgD (all below the limit of dedication ⁇ 0.01%)
  • the sorbent 1 used was a support material functionalized with pyridine-4-carboxyamide radicals and 3-carboxamidopropionic acid radicals
  • sorbent 2 was a support material functionalized with 3-indolepropionamide radicals and 4-imidazolacrylamide radicals.
  • the commercial A + 1 paste had the following composition: IgG: 77%; IgA: 7%; IgM: 3%; Albumin 12%; Transferrin 1%; Total protein content: 75%.

Abstract

L'invention concerne un procédé de séparation, de concentration et/ou de purification d'une protéine de plasma (sanguin) ou d'un constituant viral d'un mélange qui contient cette protéine de plasma (sanguin) ou le constituant viral, le mélange contenant la protéine de plasma (sanguin) ou le constituant viral étant du sang humain ou animal naturel ou un produit intermédiaire ou fini de sang humain ou animal naturel, notamment du plasma sanguin ou un produit de précipitation contenant des protéines qui a été obtenu à partir de plasma sanguin par un procédé de fractionnement, le procédé comprenant une étape de chromatographie, une filtration sur un matériau chromatographique et une étape d'inactivation du virus. Les sorbants utilisés pour la chromatographie et la filtration sont à chaque fois des matériaux supports solides dont les surfaces sont fonctionnalisées avec au moins deux molécules de récepteur. L'invention concerne notamment un procédé amélioré de purification de protéines de plasma (sanguin) de type IgG à partir de plasma humain.
PCT/EP2011/072967 2010-12-16 2011-12-15 Procédé de séparation, de concentration ou de purification d'une protéine de plasma (sanguin) ou d'un constituant viral d'un mélange WO2012080422A1 (fr)

Applications Claiming Priority (2)

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DE201010054766 DE102010054766B4 (de) 2010-12-16 2010-12-16 Verfahren zur Trennung, Aufkonzentration oder Reinigung eines (Blut)Plasmaproteins oder Virenbestandteils aus einer Mischung
DE102010054766.2 2010-12-16

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WO2012080422A1 true WO2012080422A1 (fr) 2012-06-21

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2016012803A1 (fr) * 2014-07-25 2016-01-28 Bio Products Laboratory Limited Procédé amélioré pour la préparation de l'immunoglobuline g (igg)

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DE102012022233A1 (de) * 2012-11-14 2014-05-15 Instraction Gmbh Verfahren zur Reinigung eines (Blut)plasmaproteins
DE102012022234A1 (de) * 2012-11-14 2014-05-15 Instraction Gmbh Einstufiges Verfahren zur Reinigung von (Blut)Plasmaproteinen wie Albumin aus Gemischen

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US4534972A (en) 1983-03-29 1985-08-13 Miles Laboratories, Inc. Protein compositions substantially free from infectious agents
CA1201063A (fr) 1982-07-20 1986-02-25 Winnipeg Rh Institute Inc., (The) Procede ameliore pour la preparation d'immuno- globulines igg purifiees
US4939106A (en) 1987-08-31 1990-07-03 Tdk Corporation Sintered ceramic body
US4983722A (en) 1988-06-08 1991-01-08 Miles Inc. Removal of protein A from antibody preparations
EP1141038A1 (fr) 1998-11-30 2001-10-10 instrAction GmbH Procede de preparation d'un reseau polymere
EP1232018A2 (fr) 1999-11-26 2002-08-21 instrAction GmbH Procede d'application d'un polymere sur un support
WO2004085046A2 (fr) 2003-03-25 2004-10-07 Instraction Gmbh Procede de liaison selective d'un substrat a des sorbants a l'aide de liaison au moins bivalentes
DE69823931T2 (de) 1997-06-20 2005-06-16 Bayer Corp. Chromatographieverfahren für Reinigung von IgG mit hoher Ausbeute und Virusinaktivierung

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CA1201063A (fr) 1982-07-20 1986-02-25 Winnipeg Rh Institute Inc., (The) Procede ameliore pour la preparation d'immuno- globulines igg purifiees
US4534972A (en) 1983-03-29 1985-08-13 Miles Laboratories, Inc. Protein compositions substantially free from infectious agents
US4939106A (en) 1987-08-31 1990-07-03 Tdk Corporation Sintered ceramic body
US4983722A (en) 1988-06-08 1991-01-08 Miles Inc. Removal of protein A from antibody preparations
DE69823931T2 (de) 1997-06-20 2005-06-16 Bayer Corp. Chromatographieverfahren für Reinigung von IgG mit hoher Ausbeute und Virusinaktivierung
EP1141038A1 (fr) 1998-11-30 2001-10-10 instrAction GmbH Procede de preparation d'un reseau polymere
EP1232018A2 (fr) 1999-11-26 2002-08-21 instrAction GmbH Procede d'application d'un polymere sur un support
WO2004085046A2 (fr) 2003-03-25 2004-10-07 Instraction Gmbh Procede de liaison selective d'un substrat a des sorbants a l'aide de liaison au moins bivalentes

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016012803A1 (fr) * 2014-07-25 2016-01-28 Bio Products Laboratory Limited Procédé amélioré pour la préparation de l'immunoglobuline g (igg)
US11149079B2 (en) 2014-07-25 2021-10-19 Bio Products Laboratory Limited Process for the preparation of immunoglobulin G (IgG)

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DE102010054766A1 (de) 2012-06-21

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