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WO1986006727A1 - PREPARATION D'IgG MONOMERE - Google Patents

PREPARATION D'IgG MONOMERE Download PDF

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Publication number
WO1986006727A1
WO1986006727A1 PCT/AU1986/000139 AU8600139W WO8606727A1 WO 1986006727 A1 WO1986006727 A1 WO 1986006727A1 AU 8600139 W AU8600139 W AU 8600139W WO 8606727 A1 WO8606727 A1 WO 8606727A1
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WIPO (PCT)
Prior art keywords
igg
containing material
dye
resin
fraction
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PCT/AU1986/000139
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English (en)
Inventor
Jeffrey R. Davies
Milton T. W. Hearn
Patrick B. Marley
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Commonwealth Serum Laboratories Commission
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Filing date
Publication date
Application filed by Commonwealth Serum Laboratories Commission filed Critical Commonwealth Serum Laboratories Commission
Publication of WO1986006727A1 publication Critical patent/WO1986006727A1/fr
Priority to NO870124A priority Critical patent/NO870124D0/no
Priority to DK021187A priority patent/DK21187A/da

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    • 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

  • This invention relates to a new method for the processing of normal or hyperimmune human gammaglobulin (IgG) , for example the product obtained from Cohn Fraction II or other suitable materials, whereby aggregated and. monomeric IgG are resolved to produce a product consisting essentially of monomeric IgG which can be given by intravenous injection.
  • the invention 0 further relates to various methods for the removal of contaminant proteins including IgA, IgM, plasminogen, plasmin. Factor XII, pre alli rein activator (PKA) , kallikrein and other kallikrein-like esterase activities. 5
  • the method of the present o invention allows removal of aggregated and dimeric forms from monomeric forms of immunoglobulin, all of which are usually present in IgG-rich fractions such as Cohn Fraction II, and consequently reduces so-called anticomplementary activity (ACA) , and further, allows significant removal of other contaminant proteins. notably those which can lead to the generation of kinins.
  • ACA anticomplementary activity
  • IgG immunglobulin G
  • Humoral immunity is at its weakest between the 6th and 24th months of life and continues to develop over the first twenty years of life.
  • Some humans have a poor ability to produce IgG and hence have a compromised immunity.
  • These conditions can be hereditary e.g. infantile X- chromosome linked hypogammaglobulinaemia (Bruton's disease) or be acquired, usually presenting as a selective or partial antibody deficiency syndrome.
  • Such persons normally suffer from different, frequently recurring infections and whenever possible are supplied with IgG prepared from a pool of normal donors' blood.
  • IgG Passive immunization with IgG has also become an important option in the treatment and prevention of infectious diseases, especially in cases of infection with bacteria resistant to antibiotic treatment and more recently in the treatment of idiopathic thrombocytopenic purpura. Hence, the need for a preparation of human IgG is well established and proven.
  • the intramuscular route has a number of important disadvantages compared with the intravenous route.
  • the injection volume is limited and is especially problematical in children with a small muscle mass, absorption from the injection site is relatively slow, a major proportion of the immunoglobulin is broken down by proteolysis at the site of the injection, consequently plasma levels are invariable and unpredictable, and the injection is painful.
  • the intravenous route of injection of IgG is the route of choice.
  • An important extra advantage is that more effective use of IgG can be made.
  • the dose of anti D IgG required to neutralise D Rhesus positive cells acquired from the foetus during pregnancy is several fold less when given intravenously than when given intramuscularly.
  • the earlier preparations of IgG could not be given intravenously because of the side effects they caused. (Janeway, CA. et al. , New Engl.J.Med. (1968) 278 919) .
  • Most of the preparations used presently are still not without unwanted effects and consequently are usually administered very slowly in a diluted form, especially in patients with antibody deficiency syndromes who are more sensitive to the adverse properties of IgG preparations than their normal counterparts.
  • IgG may undergo a conformational change leading to exposure -of previously cryptic sites which are then able to bind to and activate Fc receptor sites on cells and tissues. It follows that methods for the preparation of the IgG must avoid processes likely to activate the IgG and emphasizes the desirability of having IgG in the monomeric form.
  • Canadian Patent 1 137 413 discloses that by modification of these methods by carrying out the fractionations in the presence of at least one water soluble basic nitrogen-containing organic compound having a dissociation constant of 7 or less, or an acid salt of the same, a product with higher monomer content can be obtained.
  • Both plasmin treated gamma globulin and pH 4.0 gamma globulin have shorter half-lives in vivo than unmodified gamma globulin, e.g. 14-16 days compared with 20 days for unmodified IgG (Koblet, H. et al.. Vox Sang. (1967) 13.93; Merler, E. et al Vox Sang. (1967) T3 103).
  • IgG immunoglobulin G
  • ion exchange chromatography Preparative methods for immunoglobulin G (IgG) from human plasma and serum based on ion exchange chromatography are well established (Baumstark, et al, Archiv.Bio ⁇ hem. & Biophys. (1964) 108 514-522; Webb, A.J., Vox Sang. (1972) Z3 279-290).
  • DEAE cellulose to remove unwanted components such as IgG aggregates and other undesirable proteins from Cohn Fraction II to yield a product with low ACA has been described (Habeeb, A.F.S.A., et al. Vox Sang. (1977) 3_2 143-158; U.S.
  • Patent 4,312,949 as has the use of DEAE Sephadex A-50 (Patent Application PCT/US83/01016) which is claimed to be useful for the removal of prothrombin-complex proteins.
  • Purification of hyperimmune IgG such as Rho (D) and antitetanus immunoglobulin by ion exchange (DEAE Sephadex) has also been described (Hoppe, et al.. Vox Sang. (1973) 2f 308-316; Friesan, et al, J.Appl.Biochem. (1981) 3_ 164-175) and ion exchange chromatography has also been used in the purification of sulp onated monomeric IgG (Canadian Patent 1,128,418).
  • Cation exchangers such as ⁇ arboxymethylcellulose have been described for the partial resolution of IgG aggregates from monomers (Australian Patent Application No. AU A91328/82) .
  • One potential and especially desirable feature of ion exchange chromatography is its ability to . remove or reduce the levels of contaminating hepatitis B surface antigen as for example when IgG is bound onto and preferentially eluted from DEAE Sephadex or QAE Sephadex, as described in Australian Patent Application No. Au-A-17277/83.
  • a method for the purification of an IgG-containing material which comprises the steps of
  • the invention also extends to the purified IgG obtained by the above described method.
  • the microparticulate anion exchange resin may, for example, have nominal particle diameters of 3, 5, 10, 30 and 90 ⁇ , with narrow particle diameter distribution and narrow pore size distribution, based on porosity of > lOnM.
  • anion exchangers are described by Ugelstad, J., Mork, P.C., Berge, A., Ellingsen, T. and Kahn, A. . in Emulsion Polymerization, Ed. by I. Piirma, pp.383-413, Academic Press, New York, 1983.
  • the anion exchange resin is based on the material available under the trade mark Monobeads (Pharmacia Fine Chemicals), such as the Mono Q resins.
  • microparticulate quaternary and tertiary strong anionic resins such as the Mono Q resins provides:
  • silica based resins such as Accell QMA (Diosynth, Oss, Netherlands) and Spherosil QMA (Rhone Poulenc, France) and to a lesser extent the highly cross linked agarose supports such as Fast Flow Q (Pharmacia, Uppsala, Sweden) .
  • the present invention also -provides a method employing dye affinity chromatography to remove kallikrein like esterase activity from IgG-containing materials. This method may be utilized alone, or in combination with the above-described anion exchange method.
  • a method for removal of kallikrein- like esterase and other proteast enzyme or protease zymogen activity from an IgG-containing material which comprises the steps of contacting the IgG-containing material with a protein-binding dye immobilised on a macroporous, mechanically stable gel support, and recovering the purified, kallikrein-depleted IgG-containing material.
  • the invention further extends to purified IgG obtained by the above-described method.
  • the IgG-containing material is an IgG-rich material such as a Cohn Fraction II preparation (which optionally may have previously been subjected to the anion exchange step described above) .
  • the coupling of the anion exchange step with the dye affinity chromatography procedure provides a method for the rapid separation of monomeric IgG from such IgG-rich preparations with good resolution to produce an IgG preparation suitable for intravenous injection.
  • the dye affinity chromatography is carried out before the anion exchange procedure.
  • the protein-binding dye is preferably a triazinyl-dye, typically of the Procion type (ICI).
  • the matrix used in the dye affinity chromatography is a semi-rigid matrix such as Fractogel (Merck, Darmstadt, Germany) or its equivalent such as TSK (Toyo, Soda) , or Trisacryl (Retrac I.B.F., France) or a similar material.
  • Dye affinity chromatography has been used in the purification of many enzymes and proteins.
  • chlorotriazine based dyes have been used. These have been covalently attached to a variety of supports including agarose, Sephadex, beaded cellulose, metal oxides, polyacrylamide, Sephacryl S200, Spheron, glass, microparticulate silica and agarose-acrylamide (Ultragel) co-polymers (see Low, C. and Pearson, J., Methods in Enz. 104, Part C. 97-113).
  • the chlorotriazine dyes have also been used in the purification or removal of some serum proteins in laboratory scale procedures.
  • Cibacron F3GA (Ciba Geigy) coupled to agarose.
  • the Cibacron F3GA matrix has been used in the fractionation of different plasma proteins (Gianuzza, E. and Ainaud, P., Biochem J. (9182) 201 129-136), in the removal of serum albumin and lipoproteins from other serum proteins (Travis, J., and Pannell, R. , Clin.Chim.Acta. (1973) £9 49) in the purification of complement proteins (Gee, A. et al, J.Imm.Meths. (1979) 3_0_ 19) and in the purifications of a macroglobulin (Virca, G., et al.,
  • Fractogel or Trisacryl will bind 10 mg of a Procion dye from the MX series whereas 1 mL of agarose binds 2-4mg of dye (Lowe, C, and Pearson, J. Methods in Enz. 104 Part C 97-113).]
  • Various Procion dyes linked to Fractogel have been shown to bind kallikrein like activity in gammaglobulin preparations; examples of dyes suitable for high affinity binding of kallikrein-like activity from IgG preparations are Navy HER, Navy HERD, Red HE 3B, Red MX5B, Red MX8B, Scarlet MX GR and Yellow MX GR.
  • Dye affinity chromatography offers several advantages over the use of immobilized substrates such as benzamidine for the removal of kallikrein activity. These include greater protein binding capacities, a low cost, general availability, ease of coupling to matrix materials, resistance to bacterial and enzymatic degradation and low toxicity. This makes dye affinity chromatography ideal for large scale protein purification.
  • Ethanol is a major component of Cohn Fraction II paste (25%) . Consequently ethanol concentrations in the starting material can be significant. Concentrations of up to 10% ethanol have been shown to have little or no effect on resolution of components described above by both ion exchange and dye affinity chromatographies.
  • t In a typical example of the ion exchange procedure of this invention. Mono Q resin is equilibrated in 20mM Tris Cl pH 8.0 (Buffer A), 60mM NaCl.
  • the gammaglobulin solution prepared from Cohn Fraction II paste or powder is loaded onto the column and eluted from the column in Buffer A 60mM NaCl to produce a gammaglobulin solution free of aggregates, with a reduced content of dimeric gammaglobulin, low anticomplementary activity and no detectable IgA, IgM, PKA, Factor XII, plasmin or plasminogen activities.
  • a typical procedure of dye affinity chromatography employs the Procion dye such as Yellow MX GR coupled to Fractogel TSK-HW 55 (F) or TSK-HW 65 (F) .
  • This dye affinity column is equilibrated in Buffer A, 60mM NaCl.
  • the gammaglobulin solution prepared from Cohn Fraction II paste or powder is loaded onto the column and eluted from the column in Buffer A, 60mM,NaCl, to produce a gammaglobulin solution with reduced kallikrein activity.
  • a reduction of between 95 and 70% of kallikrein-like activity is seen with a high recovery of gammaglobulin.
  • the residual activity can be removed by the ion exchange procedure previously described and is probably due to the presence of PKA. This approach is illustrated by Example 2.
  • a preparation of gammaglobulin free of aggregates (trimeric or above) anticomplementary activity, PKA, Factor XII, kallikrein, plasmin and plasminogen, IgA and IgM may be achieved in accordance with this invention by combining dye affinity and ion exchange chromatography.
  • Yellow MX-GR-Fractogel and Mono Q resin is used. In this procedure the columns are equilibrated in Buffer A 60mM NaCl. The gammaglobulin solution is then passed through both columns and eluted with Buffer A 60mM NaCl to give gammaglobulin solution with the properties mentioned above.
  • the preferred order of chromatography is dye affinity chromatography followed by ion exchange chromatography, since chromatography on the dye affinity support can generate low levels of aggregate IgG and consequently increase anticomplementary activity. This is removed by the ion exchange procedure. Furthermore, any dye that leaks from the affinity column is removed by the ion exchanger.
  • Example 2 and to_a different matrix (Trisacryl. GF 2000) .
  • Chromatography was carried out on an FPLC system from Pharmacia which consisted of an LCC 500 microprocessor a UV1 control and optical unit, a REC 482 two channel chart recorder, »2 P500 pumps, a mixing chamber, an MV7 motorized valve and a 50ml superloop. All buffers were prepared using water that was quartz distilled and deionized using a Milli Q system (Millipore, Bedford, M.O. USA) . All buffers were degassed and filtered through a 0.45 ⁇ m membrane. All buffer compounds were obtained from Sigma Chemicals Co. St. Louis, Miss., USA. The ion exchanger used was the Mono Q HR 16/10 from Pharmacia.
  • the Mono Q HR 16/10 (20 ml column volume) was connected to the FPLC system and equilibrated in 20mM Tris/Cl pH 8.0 (Buffer A) 60mM NaCl. 10 gram of Cohn Fraction II paste was taken up in 30 ml of Buffer A, 60mM NaCl and filtered through a 0.45 ⁇ m membrane. The concentration of the filtered solution was 65 mg/ml. 17 ml of this solution was loaded onto the Mono Q HR 16/10 column at a flow rate of 3.0 ml/min. After loading the flow rate was increased slowly to 6 ml/min so that the back pressure, did not exceed 3.5 MPa. Non retained protein was collected, analysed by HPSEC, and assayed for proteolytic and anticomplementary activities. Table 1 compares the properties of Cohn Fraction II solution before and after processing through the Mono Q.
  • Anticomplementary activity was measured by a microtitre plate immune haemolysis method based on that in Weir (1978) (Handbook of Experimental Immunology Vol. 1 Sections 5A3-13, 3rd Ed. 1978 Blackwell) .
  • a pool of human AB sera, free of anti A, antibody served as source of complement and haemolysin and a 1.4% v/v suspension of sheep red blood cells (group ii) was used as the haemolysis indicator system.
  • the IgG was incubated with 4 CH[- n -units of complement for one hour. The results are reported as complement units "consumed" (i.e. no longer available for the haemolysis reaction) , in a one hour incubation with IgG, per mg IgG present.
  • the assay depends -on the ability of prekallikrein activator (PKA) to convert prekallikrein (extracted from human plasma) to kallikrein, and on the monitoring of kallikrein
  • PKA prekallikrein activator
  • PKA generated from Factor XII breakdown was determined by first incubating the IgG samples in the presence of prekallikrein and dextran sulphate (based on the method of Tankersley, D.L. et al. , Blood (1983) 62 ⁇ 448) and determining dextran sulphate-dependent PKA using the method described above. 4
  • Plasmin and kallikrein activities were measured spectrophotometrically ( ⁇ A405, i.e. para nitroaniline generation) using the chromogenic substrates S2251 and S2303 respectively (Kabi Vitrum, Sweden) and a Cary Model 15 spectrophotometer.
  • the Mono Q HR 16/10, the Yellow MXGR Fractogel columns (7 ml of dye - Fractogel, packed in a Pharmacia HR 10/10 column) were connected in series so that the sample was loaded onto the Mono Q column and non retained protein passed directly onto the dye-Fractogel column.
  • the columns were " equilibrated in 20mM Tris/cl pH 8.0, (Buffer -A), 60mM NaCl. 10 grams of Cohn FII paste was taken up in 30 ml ,of Buffer A, 60mM NaCl and filtered through a 0.45 ⁇ m membrane. The concentration of the filtered solution was 65 mg/ml. 12 ml of this solution was loaded onto the column.
  • the initial flow rate was 2 ml/min but was decreased to 0.5 ml/min during loading to keep back pressure below 3.5 MPa.
  • the flow rate was increased back to 2 ml/min as the back pressure dropped after loading.
  • Non retained protein was collected.
  • the non-retained protein solution contained 70% of the total protein loaded. This solution was analysed by HPSEC and assayed for anticomplementary and proteolytic enzyme activities. Table 3 compares properties of Cohn Fraction II solution with Mono Q-dye processed Cohn FII.
  • the starting material was prepared by mixing Cohn Fraction II paste with 20mM Tris/Cl ⁇ , 60mM NaCl, pH 8.0 buffer at a ratio of 1:4 to give a final protein concentration of 54mg/mL. All resins were packed into 10ml columns and pre-equilibrated in 20mM Tris Cl ⁇ , 60mM NaCl pH 8.0.
  • Red MX5B - Trisacryl processing of Cohn Fraction II solution Red MX5B was coupled to Trisacryl GF 2000 by the method described in Example 2 except that a ratio of lOg damp gel to 0.05g of dye was used in this Example. 10ml of Cohn Fraction II solution was loaded onto the column at a rate of lml/min. The non-retained peak was collected and contained 95% of the total protein loaded.
  • EXAMPLE 8 lkg of Cohn Fraction II paste was dissolved in 1.5L of 20mM Tris/Cl ⁇ , 60mM NaCl pH 8.0 buffer and filtered. The filtrate was processed through a 300 mL Yellow MX GR-Fractogel column and a HR 16/10 Mono Q column in several batches. Column eluants were pooled and acidified, and ethanol was removed and the protein concentration adjusted to 6% w/v by diafiltration. The solution was subsequently sterile filtered and analysed for IgG subclass and IgA contents.

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Abstract

Un procédé de purification d'un matériau contenant de l'IgG comprend les étapes suivantes: (i) le fractionnement d'un matériau contenant de l'immunoglobuline G sur une résine microparticulaire à fort échange d'anions ayant des surfaces mésoporeuses et macroporeuses, et (ii) la récupération par élution d'une fraction purifiée d'LgG contenue dans la résine. Le procédé peut aussi comprendre l'élimination de l'activité d'estérase similaire à la calicréine et d'autres activités zymogènes ou enzymatiques de protéase d'un matériau contenant de l'IgG par les étapes suivantes: (i) la mise en contact du matériau contenant de l'IgG avec un colorant de liaison de protéines immobilisé sur un support en un gel macroporeux mécaniquement stable, et (ii) la récupération du matériau contenant de l'IgG dépourvu d'enzymes et de zymogènes. Le matériau contenant l'IgG peut être par exemple une Fraction II de Cohn en pâte ou en poudre.
PCT/AU1986/000139 1985-05-15 1986-05-15 PREPARATION D'IgG MONOMERE WO1986006727A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
NO870124A NO870124D0 (no) 1985-05-15 1987-01-13 Fremstilling av monomert igg.
DK021187A DK21187A (da) 1985-05-15 1987-01-15 Fremgangsmaade til fremstilling af monomert igg

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Application Number Priority Date Filing Date Title
AUPH0571 1985-05-15
AUPH057185 1985-05-15

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WO1986006727A1 true WO1986006727A1 (fr) 1986-11-20

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PCT/AU1986/000139 WO1986006727A1 (fr) 1985-05-15 1986-05-15 PREPARATION D'IgG MONOMERE

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EP (1) EP0222838A4 (fr)
JP (1) JPS63500656A (fr)
DK (1) DK21187A (fr)
NZ (1) NZ216094A (fr)
WO (1) WO1986006727A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268973A3 (fr) * 1986-11-27 1989-12-27 Biotest Pharma GmbH Procédé de production d'une préparation d'immunoglobuline G intraveineuse, stable et libre de virus
DE3927111A1 (de) * 1989-08-17 1991-02-21 Biotest Pharma Gmbh Nicht modifizierte intravenoes verabreichbare igm- und/oder iga-haltige immunglobulinpraeparate und verfahren zu ihrer herstellung
EP0448075A1 (fr) * 1990-03-20 1991-09-25 Mitsubishi Rayon Co., Ltd Immunoglobuline G et procédé de sa production
US5491224A (en) * 1990-09-20 1996-02-13 Bittner; Michael L. Direct label transaminated DNA probe compositions for chromosome identification and methods for their manufacture
WO1998005686A1 (fr) * 1996-08-07 1998-02-12 Csl Limited Purification d'immunoglobulines
WO1999064462A1 (fr) * 1998-06-09 1999-12-16 Statens Serum Institut Procede de production d'immunoglobulines destinees a une administration intraveineuse et d'autres produits d'immunoglobulines
US6281336B1 (en) 1998-06-09 2001-08-28 Statens Serum Institut Process for producing immunoglobulins for intravenous administration and other immunoglobulin products
WO2015025063A1 (fr) * 2013-08-23 2015-02-26 Boehringer Ingelheim Rcv Gmbh & Co Kg Microparticules pour la rupture cellulaire et/ou la récupération de biomolécules

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US4100149A (en) * 1975-08-28 1978-07-11 Rhone-Poulenc Industries Method of separating proteins by ion exchange
US4434093A (en) * 1982-07-26 1984-02-28 Ortho Diagnostic Systems Inc. Methods for preparation of HBs Ag free gamma globulins
US4451487A (en) * 1981-05-15 1984-05-29 Boehringer Mannheim Gmbh. Process for the purification or enrichment of biologically active proteins
US4546161A (en) * 1978-01-24 1985-10-08 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Media for affinity chromatography
AU5103085A (en) * 1984-12-10 1986-06-19 Ortho Diagnostic Systems Inc. Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity

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US4136094A (en) * 1977-08-31 1979-01-23 The Regents Of The University Of Minnesota Preparation of intravenous human and animal gamma globulins and isolation of albumin
EP0064378B1 (fr) * 1981-04-27 1987-02-11 The Public Health Laboratory Service Board Chromatographie d'affinité utilisant des ions métalliques
US4639513A (en) * 1984-02-02 1987-01-27 Cuno Inc. Intravenously injectable immunoglobulin G (IGG) and method for producing same

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US4100149A (en) * 1975-08-28 1978-07-11 Rhone-Poulenc Industries Method of separating proteins by ion exchange
US4546161A (en) * 1978-01-24 1985-10-08 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Media for affinity chromatography
US4451487A (en) * 1981-05-15 1984-05-29 Boehringer Mannheim Gmbh. Process for the purification or enrichment of biologically active proteins
US4434093A (en) * 1982-07-26 1984-02-28 Ortho Diagnostic Systems Inc. Methods for preparation of HBs Ag free gamma globulins
AU5103085A (en) * 1984-12-10 1986-06-19 Ortho Diagnostic Systems Inc. Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity

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Title
Journal of Chromatography, Volume 319, No 1, issued 1985 January (Amsterdam) P. CLEZARDIN, et al "One-step Procedure for the Rapid Isolation of Mouse Monoclonal Antibodies and their Antigen Binding Fragments by Fast Protein Liquid Chromatography on a Mono Q Anion-Exchange column", see pages 67-77 *
Journal of Chromatography, Volume 359, issued 1986 May (Amsterdam), B. PAVLU, et al, "Rapid Purification of Monocloral Antibodies by High Performance Liquid Chromatography", see pages 449-460. *
Protides of the Biological Fluids, Volume 32, issued 1984 (published in 1985) by Permagon Press, P. ARNAUD et al, "Combined Pseudo-Ligard Affinity Chromotography as a General Method for Plasma Protein Purification", see pages 1117-1120 *
See also references of EP0222838A4 *
Separation News, Volume 1, published 1982, by Pharmacia Fine Chemicals AB (Uppsala), 'IgG, IgA and IgM: Improved Separation by use of the Pharmacia FPLC System'. *
Vox Sanguinis, Volume 49, issued 1985 (Basel), R.P. ZOLTON, et al, "Removal of Hepatitis B Virus Infectivity from Human gamma-Globulin Prepared by Ion-Exchange Chromatography", see pages 381-389 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268973A3 (fr) * 1986-11-27 1989-12-27 Biotest Pharma GmbH Procédé de production d'une préparation d'immunoglobuline G intraveineuse, stable et libre de virus
DE3927111A1 (de) * 1989-08-17 1991-02-21 Biotest Pharma Gmbh Nicht modifizierte intravenoes verabreichbare igm- und/oder iga-haltige immunglobulinpraeparate und verfahren zu ihrer herstellung
EP0448075A1 (fr) * 1990-03-20 1991-09-25 Mitsubishi Rayon Co., Ltd Immunoglobuline G et procédé de sa production
US5219999A (en) * 1990-03-20 1993-06-15 Mitsubishi Rayon Co., Ltd. Immunoglobulin g and process for the production thereof
US5491224A (en) * 1990-09-20 1996-02-13 Bittner; Michael L. Direct label transaminated DNA probe compositions for chromosome identification and methods for their manufacture
US6093324A (en) * 1996-08-07 2000-07-25 Csl Limited Purification of immunoglobulins
WO1998005686A1 (fr) * 1996-08-07 1998-02-12 Csl Limited Purification d'immunoglobulines
US6281336B1 (en) 1998-06-09 2001-08-28 Statens Serum Institut Process for producing immunoglobulins for intravenous administration and other immunoglobulin products
WO1999064462A1 (fr) * 1998-06-09 1999-12-16 Statens Serum Institut Procede de production d'immunoglobulines destinees a une administration intraveineuse et d'autres produits d'immunoglobulines
RU2197500C2 (ru) * 1998-06-09 2003-01-27 Статенс Серум Институт Способ получения иммуноглобулинов для внутривенного введения и другие иммуноглобулиновые продукты
EP1493751A1 (fr) * 1998-06-09 2005-01-05 Statens Serum Institut Procédé pour la préparation d'immunoglobulines pour l'administration intravéneuse et d'autres produits immunoglobuliniques
US7138120B2 (en) 1998-06-09 2006-11-21 Statens Serum Institut Process for producing immunoglobulins for intravenous administration and other immunoglobulin products
EP2270044A1 (fr) * 1998-06-09 2011-01-05 CSL Behring AG Procédé pour la préparation d'immunoglobulines pour l'administration intravéneuse et d'autres produits immunoglobuliniques
EP2272870A1 (fr) * 1998-06-09 2011-01-12 CSL Behring AG Procédé pour la préparation d'immunoglobulines pour l'administration intravéneuse et d'autres produits immunoglobuliniques
WO2015025063A1 (fr) * 2013-08-23 2015-02-26 Boehringer Ingelheim Rcv Gmbh & Co Kg Microparticules pour la rupture cellulaire et/ou la récupération de biomolécules
US10076749B2 (en) 2013-08-23 2018-09-18 Boehringer Ingelheim Rcv Gmbh & Co Kg Microparticles for cell disruption and/or biomolecule recovery
AU2014310480B2 (en) * 2013-08-23 2020-03-05 Boehringer Ingelheim Rcv Gmbh & Co Kg Microparticles for cell disruption and/or biomolecule recovery
US10661264B2 (en) 2013-08-23 2020-05-26 Boehringer Ingelheim Rcv Gmbh & Co Kg Microparticles for cell disruption and/or biomolecule recovery

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DK21187D0 (da) 1987-01-15
NZ216094A (en) 1989-06-28
EP0222838A4 (fr) 1987-12-09
DK21187A (da) 1987-03-13
JPS63500656A (ja) 1988-03-10
EP0222838A1 (fr) 1987-05-27

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