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WO1999018130A1 - Procede de purification d'immunoglobulines - Google Patents

Procede de purification d'immunoglobulines Download PDF

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Publication number
WO1999018130A1
WO1999018130A1 PCT/IL1998/000483 IL9800483W WO9918130A1 WO 1999018130 A1 WO1999018130 A1 WO 1999018130A1 IL 9800483 W IL9800483 W IL 9800483W WO 9918130 A1 WO9918130 A1 WO 9918130A1
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WIPO (PCT)
Prior art keywords
column
solution
immunoglobulins
cation exchange
purification
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IL1998/000483
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English (en)
Inventor
Israel Nur
Lily Bar
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to AU94568/98A priority Critical patent/AU9456898A/en
Publication of WO1999018130A1 publication Critical patent/WO1999018130A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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
    • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types

Definitions

  • the present invention is generally in the field of purification of immunoglobulins from a source solution and more specifically concerns purification of immunoglobulins utilizing ion-exchange resins.
  • ISG immune serum globulins
  • the final pH ranges from 4.2-5.5.
  • acid treatment Uemura, Y., J. Exp. Med, 141(3 ):337-349 (1983)
  • trypsin trypsin in low pH. All these modifications were proved to be inferior to natural intact Immunoglobulins.
  • ISG products both IMG and IVIG
  • ISG products have been considered generally safe
  • ISG products do not transmit active viruses such as those associated with hepatitis or, HIV which is associated with Acquired Immune Deficiency Syndrome (AIDS).
  • AIDS Acquired Immune Deficiency Syndrome
  • Cohn fraction II the main source of Immunoglobulins used in the 80s was contaminated with Hepatitis C.
  • a new method for virus inactivation was developed by the New York Blood Center. The method is based on the virucidal effect of an organic solvent combined with an nonionic detergent (US 4,481,189 and US 4,315,919).
  • the high amount of both the detergent and the organic solvent is toxic, therefore both have to be removed from the final formulation.
  • the purification by anion exchange resins has the disadvantages of loss of IgG sub-classes 3 and 4, as compared to the source solution.
  • purification by anion exchange resins causes the purified gamma-globulins to aggregate, which aggregates have to be eventually disassociated by digestion with trypsin and pepsin, resulting in an Ig molecule of reduced efficacy.
  • the yield of purification by anion exchange resins is usually in the range of 75 to 85% since a large amount of the immunoglobulins are not absorbed on the anion exchange resin and are thus discarded.
  • the present invention is based on the surprising finding that cation exchange resins, preferably pre-conditioned with a pH lower than 4.5, can leave a retinue of relatively large quantities of immunoglobulins as compared to anionic resins. According to the finding of the invention, it was discovered that by using cation-exchange resins, essentially all the solvent/detergent was eliminated. A further finding was that the elution at higher salt concentration and pH above 7.5 releases (eluted) all the immunoglobulins G heavy chain subclasses, notably IgG subclass 3 and 4, so that the purified immunoglobulins have a sub-class ratio similar to that of the source solution.
  • the present invention provides a method for the purification of immunoglobulins from a source solution comprising: contacting the source solution with a cation exchange resin; and - eluting the immunoglobulins bound to said cation exchange resin.
  • immunoglobulin refers to immunoglobulins in particularly IgG of all sub-classes.
  • the purification may be from any source solution such as: Cohn Fraction Paste II, PEG precipitated plasma supernatant, DEAE purified plasma effluent, ammonium sulfate precipitate of plasma or serum.
  • the purification is from a Cohn Fraction III, i.e. from a fraction obtained from blood plasma by a cold ethanol precipitation technique as specified in Technical Procedure I, hereinafter.
  • the method comprises contacting the source solution with a cation exchange resin.
  • cation exchange resin refers to a highly polymerized synthetic organic compound consisting of a large, non-diffusable anion and a simple, dif ⁇ usable cation, which latter can be exchanged for a cation in the medium in which the resin is placed.
  • Examples of cation exchange resins are any kind of matrix fiinctionalized with a carboxy, sulfo, sulfoalkyl, cyano and phenyl groups.
  • the cation exchange compound may be bound to any type of solid support including any matrix resins.
  • the cation exchange resin is constructed in the form of a chromatographic column and the method includes passing the source solution through the cation exchange chromatographic column which leads to binding of the immunoglobulins to the cation exchange resins.
  • the resin is pre-treated with an acidic solution.
  • an acidic solution it was surprisingly found that such pre-treatment facilitates binding of the immunoglobulins to the resins, increases the capacity of the cation exchange resin, and the yield of the whole process, from about 30 mg per ml of resin to 50 mg of SP resin.
  • the concept of utilizing pof the ion-exchange resin by acidic solution is contrary to the state of the art concept of using neutral ion exchange membranes. Ion exchange resins are usually cleaned by acid followed by base or vice versa.
  • the immunoglobulins are removed or "eluted" from the cation exchange resin, by rinsing it with a solution having a high salt concentration, usually in the range of 0.3 molar 1.5 molar, preferably 0.45 to 0.65 molar, most preferably 0.5 molar and having a pH in the range of 6.0-9.0, preferably 6.5 to 7.5, most preferably a pH of 7.0.
  • a solution having a high salt concentration usually in the range of 0.3 molar 1.5 molar, preferably 0.45 to 0.65 molar, most preferably 0.5 molar and having a pH in the range of 6.0-9.0, preferably 6.5 to 7.5, most preferably a pH of 7.0.
  • it is preferable to treat the source solution, prior to contact with a cation exchange resin, with an nonionic detergent and an organic solvent, in order to inactivate viruses present in the source solution as specified in U.S. 4,481,189, and U.S.
  • the source solution should be incubated with a solvent/detergent in an acidic pH, at a pH in the range of 5.1 to 5.4, preferably a pH of 5.2 for several o hours at low temperatures such as 4°C.
  • the cationic exchange chromatography serves to remove virtually all the solvent/detergent reagents. However, if it is desired to remove also various hydrophobic lipids, or lipoprotein impurities which are present in the source solution, it is possible also to pass the immunoglobulins eluted from the 5 cation exchange resins through a hydrophobic column, preferably a hydrophobic column having a substantially smaller volume than the volume of the cation exchange column, for example, 7 to 12 times smaller preferably about 10 times smaller.
  • the present invention provides a method for the 0 purification of immunoglobulins from Cohn Fraction III solution comprising: (i) diafiltratring the Cohn Fraction III solution against water; (ii) adjusting the pH of the diafiltrated solution to a pH of 5.1 to 5.4; (iii) contacting the solution obtained in (ii) with an organic solvent and a detergent; 5 (iv) passing the solution obtained in (iii) through a cation exchange chromatographic column; (v) eluting the immunoglobulins absorbed on the column by passing a solution having a salt concentration of 0.3 M - 1.5 M and a pH of 6.0-7.0.
  • step (vi) diafiltrating the elute of step (v) against water: and optionally (vii) passing the eluted immunoglobulin obtained in step (vi) through a hydrophobic column which is 7 to 12 times smaller than the cation exchange column.
  • Fig. 1 shows a schematic flow chart for the preparation of Cohn Fraction III.
  • Fig. 1 shows a schematic representation of the preparation of Cohn Fraction III.
  • Example 1 The effect of various buffers used for conditioning and elution on the concentration of IgG purified on an SP column
  • the combined mixture was loaded on a pre-conditioned FPLC (Pharmacia, Sweden) mounted with a 16 mm column loaded with 74 ml Fractogel SP (TosoHaas, Japan) resin, which is a hydrophilic methacrylate copolymer matrix functionalized with a sulphopropyl (-CH2CH 2 CH 2 SO3) group.
  • This 470x16 column as the same bed height as the large scale column.
  • the Fractogel SP column was pre-conditioned with 2 column volumes of various buffers as specified in Table 2 below, the Immunoglobulin (concentrated Cohn Fraction III prepared according to Fig. 1) mixture with the solvent detergent reagent was loaded at a rate of 1 ml/min. followed by running various elusion buffers as specified in Table 2 below. After the elusion of the SD from the mixture the protein was eluted from the SP column by various elution buffers (see Table 2).
  • Example 2 The effect on recovery and elution volume of Immunoglobulin G using three types of cationic exchange resins A. Technical procedure
  • SP0611- SP-Toyopearl 650 (M) - from Tosoh corporation Tokyo, Japan - CH 2 CH 2 CH 2 SO 3 (sulphopropyl).
  • the ionic strength of the cationic residue has a significant effect on the gel capacity.
  • the operating mechanism of ion exchange chromatography is by reversible bidning of charged molecules. Binding strength is governed by the degree of charge on the substrate - the pKa of the ion exchange matrix, and the aqueous solution properties pH and ionic strength.
  • the pKa of SP resins is 2.3 and for all the CM resin is 4.2.
  • the ion exchange capacity is 0.08-0.12 meq/ml resin for CM resin and 0.13-0.17 meq/ml resin for the SP resin.
  • the subclasses IgG distribution of the immunoglobulins in the preparation purified on the SP resin is the same as in the starting material indicating that the purification method of the invention, utilizing cation exchange resins, does not result in loss of IgG subclasses 3 and 4. This being in contrast to a significant IgG subclass 3 and 4 loss evident in purification procedures utilizing anion-exchange resins.
  • a major factor in choosing purification techniques is the ability of the technique to completely remove essentially all of the detergent, (such as X-100), which was added in order to eliminate viruses.
  • Intravenous immunoglobulin solution was prepared from frozen human plasma by means of Cohn method Fraction III followed by additional purification and virus inactivation steps (McCue et al, supra). Fraction III which contains about 3-5 mg/ml protein and 17% ethanol was concentrated by Diafiltration to 60-70 mg/ml and the salt and the ethanol were removed by 6 volumes of Diafiltration against water. The pH was adjusted to 5.2 and solution was treated by solvent / detergent (S/D) solution comprising: 0.3% Tri (n-butyl) phosphate, 1% Triton X-100 for 6 hours at 4°C.
  • S/D solvent / detergent
  • the S/D reagents were removed by cationic exchange chromatography on a 200 ml SP Toyopearl 650 resin (Tosohaas Corporation, Tokyo, Japan (-CH 2 CH 2 CH 2 SO3) sulphopropyl functional group) at low pH (4.0). At this pH, the positively charged IVIg is bound to the column, allowing the removal of the >97 of the Triton X-100 in the column spend.
  • SP Toyopearl 650 resin Tosohaas Corporation, Tokyo, Japan (-CH 2 CH 2 CH 2 SO3) sulphopropyl functional group
  • the IVIg was removed from the cationic resin by increasing the salt concentration to 0.35 molar sodium chloride and increasing the pH to 7.0. Removal of salt and concentration of protein to about 70 mg/ml was than followed by Diafiltration against water. In order to remove the lipids or lipoproteins from the IVIg solution the solution was passed through a an hydrophobic column (C-18 resin) which is 10 times smaller than the cationic column or with a ratio of 500 mg protein per ml of resin. The IVIg protein was then incubated for 22 hours at 37°C at pH 4.0 in the presence of 10% maltose in order to reduce the aggregates of Immunoglobulins. This preparation was than subjected to an addition Diafiltration against water followed by final formulation of the balk material. The final formulation consists of 10% maltose and 50 mg/ml protein at pH 5.2 . The sterile filtered bulk product is then filled in 50 ml aliquots which was stored at room temperature.
  • the cationic exchange chromatography step is highly efficient in removing the detergent reagents that are added for the purpose of viral inactivation. More than 95% Triton levels were reduced by the cationic exchange chromatography.
  • the following step of Diafiltration brought the levels below the limits specified by the toxicological studies which are > than 50 PPM of Triton X-100 and 30 PPM of TnBP in the final product of 5 mg/ml. so that even without purification on a hydrophobic column Triton levels were reduced to a medically acceptable level. Therefore it can be concluded that the hydrophobic chromatography on the C18 column is not essential but rather optional and was performed solely for the elimination of hydrophobic lipid or lipoproteins, and not for elimination of the solvent or detergent.
  • the source material for IVIg was Cohn Fraction III.
  • the fraction which contains about 3-5 mg/ml protein and 17% ethanol was concentrated by Diafiltration to 60-70 mg/ml.
  • the salt and the ethanol were removed by the ration of 6 volumes of Diafiltration against water.
  • the S/D reagents were removed by cationic exchange chromatography. At low pH (4.0) the positively charged IVIg is bound to the column. The IVIg is removed from the cationic resin by increasing the salt concentration and increasing the pH to 7.0. Concentration of the protein to 70 mg/ml and removal of salt is done by Diafiltration against water.
  • the solution is passed through a hydrophobic column which is 10 times smaller than the cationic column.
  • a sample from the S/D treated product was collected half an hour after the administration of the mixture.
  • the product sampled was eluted in the final step of column A.
  • a sample from the product which passed diafiltration was then collected and mixed well for 10 mins. before collection.
  • a sample from the effluent of the column B was collected while noting the total weight of the vessel. Initially the effluent from the column loading was collected while continuing to collect until the absorbency reaches 5%. The volume of the solution collected was determined, the sample was mixed four times and 10 ml samples were obtained for TNPP and Triton. The samples were frozen at -18°C or colder until ready for assaying. Table 7
  • the cationic exchange chromatography step is highly efflciient in removing the solvent Detergent reagents that are added at the virus inactivation step.
  • both the TNBP and Triton levels were reduced by greater than 99.8% to levels below the specified limits in the final product of 5 Vml and the tables of the SD elimination show consistency of the purification steps from batch to batch.
  • the hydrophobic column has only a marginal role in the solvent detergent removal and therefore it serves the sole purpose of elimination of lipids and lipoprotein from the product.
  • a batch of purified immunoglobulins prepared as above was transferred to Tel Ha Shomer Laboratory (Israel) for analysis.
  • Purified immunoglobulins prepared as described above were stored for 12 months at 4°C and at room temperature. Parameters tested remained stable during the year's storage at both temperatures.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention concerne un procédé permettant de purifier des immunoglobulines à partir d'une solution source et à l'aide d'une résine d'échange cationique.
PCT/IL1998/000483 1997-10-07 1998-10-02 Procede de purification d'immunoglobulines Ceased WO1999018130A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU94568/98A AU9456898A (en) 1997-10-07 1998-10-02 A method for the purification of immunoglobulins

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL121900 1997-10-07
IL12190097A IL121900A (en) 1997-10-07 1997-10-07 A method for the purification of immunoglobulins

Publications (1)

Publication Number Publication Date
WO1999018130A1 true WO1999018130A1 (fr) 1999-04-15

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PCT/IL1998/000483 Ceased WO1999018130A1 (fr) 1997-10-07 1998-10-02 Procede de purification d'immunoglobulines

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AU (1) AU9456898A (fr)
IL (1) IL121900A (fr)
WO (1) WO1999018130A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072844A3 (fr) * 2000-03-30 2002-04-11 Amersham Biosciences Ab Procédé de production d'igg
EP1225180A3 (fr) * 2001-01-17 2004-01-28 Probitas Pharma, S.A. Procédé de production de gammaglobuline G humaine à virus inactivé
WO2007067856A3 (fr) * 2005-12-06 2008-01-24 Advantek Serum Lab Ltd Procédé pour l'inactivation et la suppression du virus de la dengue dans des échantillons biologiques
JP2008540462A (ja) * 2005-05-10 2008-11-20 マレー ゴールバーン コーオペラティブ コー リミテッド 免疫グロブリン分画およびそのためのプロセス
WO2010048183A1 (fr) * 2008-10-20 2010-04-29 Abbott Laboratories Anticorps se liant à il-18 et procédés de purification de ceux-ci
WO2010064241A1 (fr) 2008-12-04 2010-06-10 Omrix Biopharmaceuticals Ltd. Administration sous-cutanée d'anticorps anti-hépatite b
US8354249B2 (en) 2005-08-11 2013-01-15 Omrix Biopharmaceuticals Ltd. Intravenous immunoglobulin composition
US8895709B2 (en) 2008-10-20 2014-11-25 Abbvie Inc. Isolation and purification of antibodies using protein A affinity chromatography
US9023994B2 (en) 2011-05-16 2015-05-05 Omrix Biopharmaceuticals, Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
US9109010B2 (en) 2008-10-20 2015-08-18 Abbvie Inc. Viral inactivation during purification of antibodies cross reference to related applications
US9631007B2 (en) 2005-05-25 2017-04-25 Hoffmann-La-Roche Inc. Method for the purification of antibodies
EP2061803B1 (fr) 2006-08-28 2019-08-14 Ares Trading S.A. Procédé de purification de protéines contenant fc
CN112574296A (zh) * 2020-12-30 2021-03-30 中国医学科学院输血研究所 一种模拟IVIg的多人份混合人血浆IgG样品的分离纯化方法
WO2022161889A1 (fr) 2021-01-27 2022-08-04 Centre National De La Recherche Scientifique Procede de fabrication d'un detecteur des flux d'un premier et d'un deuxieme rayonnements ionisants

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4877866A (en) * 1986-11-27 1989-10-31 Biotest Pharma Gmbh Method of producing a virus safe, storage-stable, and intravenously tolerable immunoglobulin-G preparation
EP0440483A2 (fr) * 1990-02-01 1991-08-07 Baxter International Inc. Procédé de préparation d'immunoglobulines de sérum
EP0525502A1 (fr) * 1991-08-02 1993-02-03 Octapharma Ag Procédé pour la fabrication de solutions contenant des immunoglobulines et des viruses inactivés
EP0530447A2 (fr) * 1991-06-08 1993-03-10 Biotest Pharma Gmbh Procédé de purification d'anticorps monoclonaux du type IgG et leur application
US5429746A (en) * 1994-02-22 1995-07-04 Smith Kline Beecham Corporation Antibody purification

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4877866A (en) * 1986-11-27 1989-10-31 Biotest Pharma Gmbh Method of producing a virus safe, storage-stable, and intravenously tolerable immunoglobulin-G preparation
EP0440483A2 (fr) * 1990-02-01 1991-08-07 Baxter International Inc. Procédé de préparation d'immunoglobulines de sérum
EP0530447A2 (fr) * 1991-06-08 1993-03-10 Biotest Pharma Gmbh Procédé de purification d'anticorps monoclonaux du type IgG et leur application
EP0525502A1 (fr) * 1991-08-02 1993-02-03 Octapharma Ag Procédé pour la fabrication de solutions contenant des immunoglobulines et des viruses inactivés
US5429746A (en) * 1994-02-22 1995-07-04 Smith Kline Beecham Corporation Antibody purification

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072844A3 (fr) * 2000-03-30 2002-04-11 Amersham Biosciences Ab Procédé de production d'igg
US6835379B2 (en) 2000-03-30 2004-12-28 Amersham Biosciences Ab Method of producing IgG
EP1225180A3 (fr) * 2001-01-17 2004-01-28 Probitas Pharma, S.A. Procédé de production de gammaglobuline G humaine à virus inactivé
US6875848B2 (en) 2001-01-17 2005-04-05 Probitas Pharma, S.A. Process for the production of virus-inactivated human gammaglobulin G
JP2008540462A (ja) * 2005-05-10 2008-11-20 マレー ゴールバーン コーオペラティブ コー リミテッド 免疫グロブリン分画およびそのためのプロセス
US11034754B2 (en) 2005-05-25 2021-06-15 Hoffmann-La Roche Inc. Method for the purification of antibodies
US9631007B2 (en) 2005-05-25 2017-04-25 Hoffmann-La-Roche Inc. Method for the purification of antibodies
US8354249B2 (en) 2005-08-11 2013-01-15 Omrix Biopharmaceuticals Ltd. Intravenous immunoglobulin composition
US9365635B2 (en) 2005-08-11 2016-06-14 Omrix Biopharmaceuticals Ltd. Intravenous immunoglobulin composition
WO2007067856A3 (fr) * 2005-12-06 2008-01-24 Advantek Serum Lab Ltd Procédé pour l'inactivation et la suppression du virus de la dengue dans des échantillons biologiques
EP2061803B2 (fr) † 2006-08-28 2022-11-16 Ares Trading S.A. Procédé de purification de protéines contenant fc
EP2061803B1 (fr) 2006-08-28 2019-08-14 Ares Trading S.A. Procédé de purification de protéines contenant fc
US9018361B2 (en) 2008-10-20 2015-04-28 Abbvie Inc. Isolation and purification of antibodies using protein a affinity chromatography
WO2010048183A1 (fr) * 2008-10-20 2010-04-29 Abbott Laboratories Anticorps se liant à il-18 et procédés de purification de ceux-ci
US9109010B2 (en) 2008-10-20 2015-08-18 Abbvie Inc. Viral inactivation during purification of antibodies cross reference to related applications
AU2009307728B2 (en) * 2008-10-20 2014-12-11 Abbvie Inc. Antibodies that bind to IL-18 and methods of purifying the same
US8895709B2 (en) 2008-10-20 2014-11-25 Abbvie Inc. Isolation and purification of antibodies using protein A affinity chromatography
US8795671B2 (en) 2008-12-04 2014-08-05 Omrix Biopharmaceuticals Ltd. Subcutaneous administration of anti-hepatitis B antibodies
WO2010064241A1 (fr) 2008-12-04 2010-06-10 Omrix Biopharmaceuticals Ltd. Administration sous-cutanée d'anticorps anti-hépatite b
US9657087B2 (en) 2008-12-04 2017-05-23 Omrix Biopharmaceuticals Ltd. Subcutaneous administration of anti-hepatitis B antibodies
US9796770B2 (en) 2011-05-16 2017-10-24 Omrix Biopharmaceuticals Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
US9023994B2 (en) 2011-05-16 2015-05-05 Omrix Biopharmaceuticals, Ltd. Immunoglobulin reduced in thrombogenic agents and preparation thereof
EP3572419A1 (fr) 2011-05-16 2019-11-27 Omrix Biopharmaceuticals Ltd. Immunoglobuline à teneur réduite en agents thrombogéniques et sa préparation
CN112574296A (zh) * 2020-12-30 2021-03-30 中国医学科学院输血研究所 一种模拟IVIg的多人份混合人血浆IgG样品的分离纯化方法
CN112574296B (zh) * 2020-12-30 2023-05-19 中国医学科学院输血研究所 一种模拟IVIg的多人份混合人血浆IgG样品的分离纯化方法
WO2022161889A1 (fr) 2021-01-27 2022-08-04 Centre National De La Recherche Scientifique Procede de fabrication d'un detecteur des flux d'un premier et d'un deuxieme rayonnements ionisants

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IL121900A (en) 2001-12-23
IL121900A0 (en) 1998-03-10
AU9456898A (en) 1999-04-27

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