USRE31268E - Method of recovering immunoglobulin using a polyol and an alkanoic acid - Google Patents

Method of recovering immunoglobulin using a polyol and an alkanoic acid Download PDF

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Publication number
USRE31268E
USRE31268E US06/292,386 US29238681A USRE31268E US RE31268 E USRE31268 E US RE31268E US 29238681 A US29238681 A US 29238681A US RE31268 E USRE31268 E US RE31268E
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US
United States
Prior art keywords
acid
polyol
alkanoic acid
precipitation
carbon atoms
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Expired - Lifetime
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US06/292,386
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English (en)
Inventor
Jorgen F. Hansen
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Nordisk Insulinlaboratorium
Hemasure Inc
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Nordisk Insulinlaboratorium
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Assigned to HEMAPHARM, INC. reassignment HEMAPHARM, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVO NORDISK A/S
Assigned to HEMASURE, INC. reassignment HEMASURE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HEMAPHARM, INC.
Expired - Lifetime 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

Definitions

  • the present invention relates to a method of recovering immunoglobulin suitable for intravenous administration, by fractionated precipitation of blood plasma, serum or a fraction thereof with a polycondensed di or polyol.
  • Immunoglobulins comprising gammaglobulins have therapeutic merit as they are suitable for preparing immunizing preparations.
  • Immunoglobulin is found in blood plasma of animal origin, from which it may be recovered by various precipitation and purification processes. Hence, gammaglobulin can be recovered as concentrated solutions by a method developed by Cohn et al, cf. J. Clin. Invest. Chem. Soc., 68, 479-75 (1946). According to Cohn, it is possible to obtain a fraction II being a 16.5% concentrate and which may be injected intramuscularly.
  • Cohn's method comprises precipitation with alcohol which has a water-expelling effect and may lead to irreversible denaturation, whereby the globulin is rendered anti-complementary. It has been attempted to avoid this by means of special separation processes and/or by chemical modification of the gammaglobulin.
  • the prior art teaches an improved fractionating process in which the gammaglobulin is precipitated from blood plasma by means of polyethylene glycol (PEG) as precipitant, cf. U.S. Pat. No. 3,415,804. This eliminates the undesired denaturation, but the purity of the precipated product is unsatisfactory.
  • PEG polyethylene glycol
  • this precipitation process may be improved by replacing polyethylene glycol by a block copolymer of ethylene oxide and polyoxypropylene polymer of a further specified nature and observing some specific precipitation conditions.
  • the present invention is based on the observation that the fractionated precipitation of immunoglobulins, also known as gammaglobulins, by means of polyethylene glycol or other polycondensed di or polyol may be rendered appreciably more specific if the precipitation is carried out in the presence of a mono or polyalkanoic acid having from .[.4 to 12.]. .Iadd.6 to 9 .Iaddend.carbon atoms, whereby i.a. fibrinogen and lipoproteins are removed.
  • the claimed method may be used in connection with any polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, preferably 4000 to 6000, or polypropylene glycol. Also copolymers of ethylene oxide with propylene oxide or polyethers are suitable. .[.Suitable as mono or polyalkanoic acid is any alkanoic acid having from 4 to 12 carbon atoms..]. Preferred according to the invention is an alkanoic acid having from 6 to 9 carbon atoms, preferably caprylic acid. Examples of other suitable alkanoic acids are caproic acid and nonanic acid. Also branched alkanoic acids may be used.
  • any polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, preferably 4000 to 6000, or polypropylene glycol.
  • copolymers of ethylene oxide with propylene oxide or polyethers are suitable.
  • alkanoic acids When using higher alkanoic acids, .[.such as having from 9 to 12 carbon atoms,.]. it may be advantageous to incorporate additionally one or more carboxyl groups with a view to improving water-solubility. The same effect is achieved by using alkanoic acids having substituents containing, for example, one or more hydroxyl groups or amino groups.
  • the immunoglobulin-containing solution is advantageously mixed with from 1 to 8 percent by weight of polyethylene glycol or other polycondensed diol or polyol together with from 0.1 to 5 percent by weight of caprylic acid or other alkanoic acid having from .[.4 to 12.]. .Iadd.6 to 9 .Iaddend.carbon atoms, the precipitation with alkanoic acid according to the invention being advantageously effected at a pH of from 3 to 7, preferably from 4.5 to 5.5.
  • the solution is filtered until clear using a Seitz EK-filter.
  • the solution formed is admixed with 5 g of caprylic acid and 30 g of PEG 3000 per liter solution, and adjusted to a pH of 4.9. After leaving to stand for 2 hours at 20° C. the mixture is centrifugated, and the liquid phase is filtered to obtain a clear solution.
  • the yield of product is 60 percent.
  • the degree of purity as determined by DISC PAGE discloses substantially only two bands corresponding to IgG and IgM, respectively. The analysis is performed by application of 500 ⁇ g of product.
  • the purified product may, if desired, be converted to an intravenously injectable preparation by dissolution in 0.9 percent sodium chloride solution until a protein concentration of about 5 percent.
  • the preparation is distinguished by an extremely low anticomplementary activity, for which reason it is particularly suitable for intravenous administration.
  • Example 2 The procedure according to Example 1 is repeated, except that the human blood plasma is replaced by swine plasma.
  • Example 1 The procedure according to Example 1 is repeated, except that human blood plasma is replaced by blood serum.
  • 100 l of plasma or serum are mixed with 100 l of 600 g/l PEG 3000 solution.
  • the pH is adjusted to 6.5.
  • the precipitate is separated by centrifugation and redissolved in 100 l of distilled water admixed with 0.015 M of NaCl.
  • the pH is adjusted to 5.0.
  • the precipitate is separated by centrifugation.
  • the centrifugate is admixed with additional 40 g of PEG 3000 per liter.
  • the pH is adjusted to 7.5.
  • the precipitate is separated by centrifugation and redissolved in distilled water with 0.002 M of NaCl.
  • the solution is filtered to clarity (e.g. SEITZ ® EK-Filter).
  • the protein concentration should be 50-100 g/l.
  • 20 g of DEAE-Sephadex-A25 ® are added per 100 g of protein.
  • the DEAE-Sephadex is separated by filtration.
  • the DEAE-Sephadex treatment is repeated. After sterile filtration there is obtained an immunoglobulin G preparation free from anticomplementariness and suitable for intravenous administration.

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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)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
US06/292,386 1976-04-06 1981-08-13 Method of recovering immunoglobulin using a polyol and an alkanoic acid Expired - Lifetime USRE31268E (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1628/76 1976-04-06
DK162876AA DK139056B (da) 1976-04-06 1976-04-06 Fremgangsmåde til udvinding af immunoglobulin, der er egnet til intravenøs indgivelse.

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US78225577A Continuation 1976-04-06 1977-03-28
US05/914,456 Reissue US4164495A (en) 1976-04-06 1978-06-12 Method of recovering immunoglobulin using a polyol and an alkanoic acid

Publications (1)

Publication Number Publication Date
USRE31268E true USRE31268E (en) 1983-06-07

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Family Applications (1)

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US06/292,386 Expired - Lifetime USRE31268E (en) 1976-04-06 1981-08-13 Method of recovering immunoglobulin using a polyol and an alkanoic acid

Country Status (20)

Country Link
US (1) USRE31268E (enrdf_load_stackoverflow)
JP (1) JPS52122620A (enrdf_load_stackoverflow)
AR (1) AR211890A1 (enrdf_load_stackoverflow)
AU (1) AU511474B2 (enrdf_load_stackoverflow)
BE (1) BE852995A (enrdf_load_stackoverflow)
CA (1) CA1072444A (enrdf_load_stackoverflow)
CH (1) CH628813A5 (enrdf_load_stackoverflow)
DD (1) DD129451A5 (enrdf_load_stackoverflow)
DE (1) DE2713817A1 (enrdf_load_stackoverflow)
DK (1) DK139056B (enrdf_load_stackoverflow)
ES (1) ES457482A1 (enrdf_load_stackoverflow)
FI (1) FI61191C (enrdf_load_stackoverflow)
FR (1) FR2347379A1 (enrdf_load_stackoverflow)
GB (1) GB1551865A (enrdf_load_stackoverflow)
HU (1) HU175511B (enrdf_load_stackoverflow)
IL (1) IL51782A (enrdf_load_stackoverflow)
IT (1) IT1075148B (enrdf_load_stackoverflow)
NL (1) NL7703572A (enrdf_load_stackoverflow)
NO (1) NO146763C (enrdf_load_stackoverflow)
SE (1) SE7703843L (enrdf_load_stackoverflow)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043427A (en) * 1988-06-07 1991-08-27 Foundation Nationale De Transfusion Sanguine Process and installation for continuously fractionating plant, animal or human proteins
US5367054A (en) * 1993-04-12 1994-11-22 Stolle Research & Development Corp. Large-scale purification of egg immunoglobulin
US5525519A (en) * 1992-01-07 1996-06-11 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
US20050272917A1 (en) * 2004-05-14 2005-12-08 Hematech, Llc Methods for immunoglobulin purification
US20060226086A1 (en) * 2005-04-08 2006-10-12 Robinson Thomas C Centrifuge for blood processing systems
US20090292109A1 (en) * 2008-04-16 2009-11-26 Biogen Idec Ma Inc. Method of Isolating Biomacromolecules Using Polyalkylene Glycol and Transition Metals
US20100145022A1 (en) * 2006-11-01 2010-06-10 Biogen Idic Ma Inc. Method of Isolating Biomacromolecules Using Low pH and Divalent Cations

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5625114A (en) * 1979-08-07 1981-03-10 Green Cross Corp:The Preparation of human gamma globulin
US4590002A (en) * 1984-12-10 1986-05-20 Ortho Diagnostic Systems, Inc. Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity
FR2578425B1 (fr) * 1985-03-07 1988-06-10 Nal Transfusion Sanguine Centr Preparations d'immunoglobulines presentant des titres eleves en anticorps bloquants anti-allergenes, leur preparation et leurs applications pour le traitement d'allergies
CA1308023C (en) * 1988-07-29 1992-09-29 William Austin James Mcauley Immunoglobulin extraction utilizing properties of colloidal solutions

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3100737A (en) * 1958-02-05 1963-08-13 Auerswald Wilhelm Method of preparing a plasma protein solution free of active hepatitis virus and product produced thereby
US3415804A (en) * 1962-01-03 1968-12-10 South African Inventions Fractionation of mixtures of proteinaceous substances using polyethylene glycol
US3686395A (en) * 1966-04-06 1972-08-22 Biotest Serum Institut Gmbh Process for preparation of storage stable hepatitis-free serum
US3770631A (en) * 1971-06-29 1973-11-06 Baxter Laboratories Inc Clarification of blood serum and plasma
US3808189A (en) * 1973-03-15 1974-04-30 American Cyanamid Co Isolation of gamma globulin preparations enriched in iga and igm using polyethylene glycol
US3869436A (en) * 1971-06-01 1975-03-04 Statens Bakteriologiska Lab Method for fractionating plasma proteins using peg and ion-exchangers
US3876775A (en) * 1972-06-19 1975-04-08 Cutter Lab Stable intravenously injectable plasma protein free from hypotensive effects and process for its production
US3880989A (en) * 1973-01-30 1975-04-29 Baxter Laboratories Inc Production of antisera comprising fractionating plasma or serum with an ethylene oxide-polyoxypropylene block copolymer
US3916026A (en) * 1968-09-19 1975-10-28 Biotest Serum Institut Gmbh Method for the preparation of gamma-globulin suitable for intravenous use
US4017470A (en) * 1974-02-18 1977-04-12 The Green Cross Corporation Method for preparing a heat-stable plasma protein solution from paste IV-1
US4021540A (en) * 1975-07-28 1977-05-03 Ortho Diagnostics Inc. Preparation of a hepatitis B immune globulin and use thereof as a prophylactic material
US4075193A (en) * 1976-11-26 1978-02-21 Parke, Davis & Company Process for producing intravenous immune globulin
US4082734A (en) * 1975-06-18 1978-04-04 Biotest-Serum-Institut Gmbh Production of intravenously applicable native human immune globulin having a normal half-life
US4093606A (en) * 1975-02-18 1978-06-06 Coval M L Method of producing intravenously injectable gamma globulin and a gamma globulin suitable for carrying out the method
US4124576A (en) * 1976-12-03 1978-11-07 Coval M L Method of producing intravenously injectable gamma globulin
US4154819A (en) * 1975-09-06 1979-05-15 Biotest-Serum-Institut Gmbh Preparation of a gamma-globulin solution suitable for intravenous administration using diketene

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3100737A (en) * 1958-02-05 1963-08-13 Auerswald Wilhelm Method of preparing a plasma protein solution free of active hepatitis virus and product produced thereby
US3415804A (en) * 1962-01-03 1968-12-10 South African Inventions Fractionation of mixtures of proteinaceous substances using polyethylene glycol
US3686395A (en) * 1966-04-06 1972-08-22 Biotest Serum Institut Gmbh Process for preparation of storage stable hepatitis-free serum
US3916026A (en) * 1968-09-19 1975-10-28 Biotest Serum Institut Gmbh Method for the preparation of gamma-globulin suitable for intravenous use
US3869436A (en) * 1971-06-01 1975-03-04 Statens Bakteriologiska Lab Method for fractionating plasma proteins using peg and ion-exchangers
US3770631A (en) * 1971-06-29 1973-11-06 Baxter Laboratories Inc Clarification of blood serum and plasma
US3876775A (en) * 1972-06-19 1975-04-08 Cutter Lab Stable intravenously injectable plasma protein free from hypotensive effects and process for its production
US3880989A (en) * 1973-01-30 1975-04-29 Baxter Laboratories Inc Production of antisera comprising fractionating plasma or serum with an ethylene oxide-polyoxypropylene block copolymer
US3808189A (en) * 1973-03-15 1974-04-30 American Cyanamid Co Isolation of gamma globulin preparations enriched in iga and igm using polyethylene glycol
US4017470A (en) * 1974-02-18 1977-04-12 The Green Cross Corporation Method for preparing a heat-stable plasma protein solution from paste IV-1
US4093606A (en) * 1975-02-18 1978-06-06 Coval M L Method of producing intravenously injectable gamma globulin and a gamma globulin suitable for carrying out the method
US4082734A (en) * 1975-06-18 1978-04-04 Biotest-Serum-Institut Gmbh Production of intravenously applicable native human immune globulin having a normal half-life
US4021540A (en) * 1975-07-28 1977-05-03 Ortho Diagnostics Inc. Preparation of a hepatitis B immune globulin and use thereof as a prophylactic material
US4154819A (en) * 1975-09-06 1979-05-15 Biotest-Serum-Institut Gmbh Preparation of a gamma-globulin solution suitable for intravenous administration using diketene
US4075193A (en) * 1976-11-26 1978-02-21 Parke, Davis & Company Process for producing intravenous immune globulin
US4124576A (en) * 1976-12-03 1978-11-07 Coval M L Method of producing intravenously injectable gamma globulin

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Encycl. of Chemistry, 3rd Ed. (1973), pp. 466-477, Hampel et al. *
J. of Immunology, 1962, Frommhagen et al., pp. 336-343 (1962). *
Rev. Franc. Etudes Clin. et Biol. 1969, XIV, pp. 1054-1058, Steinbuch et al. *
Vox Sang., 34:143-148 (1978), Gislason et al. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043427A (en) * 1988-06-07 1991-08-27 Foundation Nationale De Transfusion Sanguine Process and installation for continuously fractionating plant, animal or human proteins
US5525519A (en) * 1992-01-07 1996-06-11 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
US5599719A (en) * 1992-01-07 1997-02-04 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
US5367054A (en) * 1993-04-12 1994-11-22 Stolle Research & Development Corp. Large-scale purification of egg immunoglobulin
US20050272917A1 (en) * 2004-05-14 2005-12-08 Hematech, Llc Methods for immunoglobulin purification
US20060226086A1 (en) * 2005-04-08 2006-10-12 Robinson Thomas C Centrifuge for blood processing systems
US20100145022A1 (en) * 2006-11-01 2010-06-10 Biogen Idic Ma Inc. Method of Isolating Biomacromolecules Using Low pH and Divalent Cations
US9109015B2 (en) 2006-11-01 2015-08-18 Biogen Ma Inc Method of isolating biomacromolecules using low pH and divalent cations
US20090292109A1 (en) * 2008-04-16 2009-11-26 Biogen Idec Ma Inc. Method of Isolating Biomacromolecules Using Polyalkylene Glycol and Transition Metals

Also Published As

Publication number Publication date
DK139056C (enrdf_load_stackoverflow) 1979-05-21
FI61191B (fi) 1982-02-26
CA1072444A (en) 1980-02-26
FR2347379B1 (enrdf_load_stackoverflow) 1981-11-20
GB1551865A (en) 1979-09-05
FR2347379A1 (fr) 1977-11-04
IT1075148B (it) 1985-04-22
DD129451A5 (de) 1978-01-18
NO146763C (no) 1982-12-08
DK162876A (enrdf_load_stackoverflow) 1977-10-07
NL7703572A (nl) 1977-10-10
IL51782A0 (en) 1977-05-31
CH628813A5 (en) 1982-03-31
FI771071A7 (enrdf_load_stackoverflow) 1977-10-07
DE2713817A1 (de) 1977-10-27
HU175511B (hu) 1980-08-28
SE7703843L (sv) 1977-10-07
AU2391077A (en) 1978-10-12
JPS52122620A (en) 1977-10-15
FI61191C (fi) 1982-06-10
AR211890A1 (es) 1978-03-31
ES457482A1 (es) 1978-03-16
IL51782A (en) 1980-12-31
NO771225L (no) 1977-10-07
AU511474B2 (en) 1980-08-21
DK139056B (da) 1978-12-11
NO146763B (no) 1982-08-30
BE852995A (fr) 1977-07-18

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Owner name: HEMAPHARM, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVO NORDISK A/S;REEL/FRAME:011821/0254

Effective date: 19960502

AS Assignment

Owner name: HEMASURE, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HEMAPHARM, INC.;REEL/FRAME:011846/0341

Effective date: 20010521