EP1326893A2 - Fraction de plasma renfermant de la bikunine, son procede de fabrication et son utilisation - Google Patents

Fraction de plasma renfermant de la bikunine, son procede de fabrication et son utilisation

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Publication number
EP1326893A2
EP1326893A2 EP01986698A EP01986698A EP1326893A2 EP 1326893 A2 EP1326893 A2 EP 1326893A2 EP 01986698 A EP01986698 A EP 01986698A EP 01986698 A EP01986698 A EP 01986698A EP 1326893 A2 EP1326893 A2 EP 1326893A2
Authority
EP
European Patent Office
Prior art keywords
bikunin
plasma fraction
plasma
proteins
fraction
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.)
Withdrawn
Application number
EP01986698A
Other languages
German (de)
English (en)
Inventor
Djuro Josic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Octapharma AG
Original Assignee
Octapharma AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Octapharma AG filed Critical Octapharma AG
Publication of EP1326893A2 publication Critical patent/EP1326893A2/fr
Withdrawn legal-status Critical Current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
    • C07K16/38—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against protease inhibitors of peptide structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8114—Kunitz type inhibitors

Definitions

  • Plasma fraction containing bikunin process for its preparation and its use
  • the invention relates to a method for producing a bikunin-containing plasma fraction, the available product and its use in septic conditions.
  • Bikunin is a proteinase inhibitor with a number of physiological functions. It is mostly present in plasma as a subunit of pre- and inter- ⁇ -tr ⁇ spin inhibitor (I ⁇ l). However, less bikunin activity is found in the bound form than in the free form.
  • the diverse activities of Bikunin also include the inhibition of plasmin on the cell surface and the stimulation of neutrophils by lipopolysaccharides, which indicates a role in inflammatory reactions. The structure and function of Bikunin is discussed in "The International Journal of Biochemistry Cell Biology" 32, 125-137 (2000).
  • Bikunin is often referred to as the light chain of l ⁇ l or as its subunit 1.
  • l ⁇ l family of plasma proteins which consists of various structurally related molecules. An overview of this is provided by J.P. Salier et ai (Biochem. J. 315, 1-9 (1996)).
  • Bikunin is integrated with various heavy (H) chains by covalent bonding to form l ⁇ l.
  • H heavy chains by covalent bonding to form l ⁇ l.
  • a protein glycosaminoglycan-protein bond is formed via chondroitin-4-sulfate.
  • an inter- ⁇ -trypsin inhibitor concentrate is described in US Pat. No. 5,777,081, which consists of three peptide chains and has a molecular weight of approximately 220 kD.
  • This molecule consists of the two heavy chains Hl and H2, as well as the light chain, Bikunin, bound by a glycosaminoglycan chain.
  • Heparin affinity chromatography is used to obtain the concentrate.
  • the technical problem on which the invention is based is the provision of a plasma fraction with antitrypsin activity which is distinguished by a simple production process and the effectiveness in septic conditions.
  • this problem is solved by a new production process for a human bikunin plasma fraction. Due to the bikunin content, this plasma fraction has antitrypsin activity. It has been found that molecular exclusion chromatography is extremely suitable for obtaining the bikunin plasma fraction. A variety of proteins from the l ⁇ l family can thus be obtained together. Among them is the native inter- ⁇ -trypsin inhibitor, which is often found in plasma associated with other high molecular weight proteins containing bikunin.
  • a pure inter- ⁇ -trypsin inhibitor is also obtainable with the method according to the invention, which essentially consists only of the molecule with the three peptide chains (Hl, H2 and bikunin), bound by a glycosaminoglycan chain, and a molecular weight of about 220 has kDa.
  • Free unbound bikunin has a molecular weight of less than 70 kDa and is easily removed by the process according to the invention.
  • the free unbound bikunin has the disadvantage of a short half-life of around 30 minutes. Bikunin in the plasma fraction according to the invention proves to be considerably more stable in vivo; a half-life of several hours could be demonstrated.
  • bikunin which is present in bound form in the plasma fraction produced according to the invention, is found in an in vivo Model shows as a valuable therapeutic against sepsis.
  • cryoprecipitate as the starting material for the production of the bikunin plasma fraction according to the invention has the advantage that, in addition to the bikunin plasma fraction, a further therapeutically relevant plasma fraction containing purified complex of blood coagulation factor VIII (FVIII) and von Willebrand factor (vWF) is included in the molecular exclusion chromatography. the FVIII / vWF, can be won.
  • FVIII blood coagulation factor VIII
  • vWF von Willebrand factor
  • Molecular exclusion chromatography preferably follows purification of the FVIII / vWF by ion exchange chromatography.
  • the particularly preferred combination of purification and manufacturing processes is anion exchange chromatography for purification of plasma proteins from cryoprecipitate, e.g. the FVIII and / or the vWF, and a subsequent gel permeation.
  • the purification of factors of the prothrombin complex and the gel permeation are also preferred.
  • chromatography processes can be used to increase the purity of the proteins containing bikunin. These include ion exchange, affinity, molecular exclusion chromatography and / or hydrophobic chromatography.
  • Chromatography materials based on hydrophilic supports are preferably used for gel permeation or molecular exclusion chromatography. These are preferably polysaccharides, in particular dextrans, cellulose, agarose, modified polysaccharides, hydrophilic, synthetic polymers, preferably so-called tentacle gels, silica gels modified with hydrophilic groups or combinations thereof.
  • the bikunin plasma fraction is eluted primarily with buffers with an increased salt concentration in a pH range of about 6 to 9.
  • Polysaccharides such as Sephadex, Sepharose, Agarose, etc. are used as commercially available carriers.
  • Preferred synthetic polymers are those based on polyglycidyl methacrylate, in particular modified with hydrophilic arms (tentacles).
  • Patentacles For further description, reference is made to EP-A-0 337 144 and EP-A-0 320 023.
  • the support materials from EP-A-0 377 144 are particularly preferred as tentacle chromatography materials.
  • inorganic materials such as silica gels can also be used.
  • TSK gels and so-called SW gels silicon wide pore, Toso Haas, Stuttgart
  • the carrier material used in the method according to the invention in particular has a large-pore structure.
  • Particulate material in particular has a grain size of 0.5 to 350 ⁇ m.
  • So-called compact block materials, membranes and / or monoliths, as described in EP-A-0 320 023, can also be used.
  • the compact block material has the advantage that it. is stable due to its monolithic structure and can be operated in a radial flow or in a continuous process.
  • the process time is significantly reduced, which has the advantage that an unstable protein, such as the l ⁇ l, can possibly also be purified without the use of process stabilizers, and the native state is essentially maintained.
  • the Rapid chromatographic separation on such materials is also used on a small scale.
  • the method according to the invention is therefore not only made available for large-scale industrial use, but also for analysis, for example as part of a process control during the production of plasma fractions.
  • the pore size of the carrier material is usually in the range from 5 nm to 10 ⁇ m, in particular greater than 50 ⁇ m.
  • ion exchangers on an organic or inorganic basis ie cation or anion exchangers
  • strong cation exchangers are supports with SO 3 groups and weak carboxymethyl cation exchangers.
  • the strong anion exchangers that may be used include, for example, the gels provided with TMAE or QA groups; to the strong anion exchangers, for example, those with DEAE groups. In general, tentacle gels or membranes can be used.
  • affinity materials with different ligands such as heparins, dextransuates, hydroxyapatites, lectins, receptors and low-molecular substances with affinity for l ⁇ l or bikunin, can also be used.
  • affinity materials with different ligands such as heparins, dextransuates, hydroxyapatites, lectins, receptors and low-molecular substances with affinity for l ⁇ l or bikunin
  • supports are used which are modified with linear hydrocarbons with Cl to C10 or their derivatives, including phenyl groups and the like.
  • a particularly suitable method according to the invention uses immunoaffinity chromatography using a monoclonal antibody against bikunin. This further enriches molecules that have bound Bikunin.
  • a preferred monoclonal antibody is a mouse. Antibody directed against an epitope in the active center of Bikunin. Such an antibody, such as Mab 69.31, in particular blocks the plasmin-inhibiting effect of the light chain of l ⁇ l.
  • the monoclonal antibody that binds to the bikunin-containing proteins of the l ⁇ l family is particularly suitable for the production and further purification of the bikunin plasma fraction according to the invention.
  • polyclonal antibodies can also be obtained by immunizing suitable systems with the bikunin plasma fraction according to the invention.
  • Analysis of the bikunin plasma fraction using electrophoretic and immunochemical methods shows a number of bikunin-containing proteins, at least those that contain bikunin associated with at least one heavy chain of the l ⁇ l. Free bikunin could not be found.
  • the bikunin plasma fraction or l ⁇ l plasma fraction obtained according to the invention is thus essentially free of unbound, separate bikunin.
  • the bikunin plasma fraction according to the invention can also be characterized in that it largely consists of proteins which have an antitrypsin activity.
  • a preferred plasma fraction therefore contains at least 70% proteins with an antitrypsin activity, preferably at least 80%, most preferably at least 90%.
  • Specific purification steps can also be used to express a specific activity, expressed in trypsin inhibiting units per milligram protein, which is a multiple of the activity of human plasma.
  • the antitrypsin activity can be achieved at least 50 times more than in plasma, preferably more than 100 times, most preferably more than 200 times as much as in human plasma.
  • the method according to the invention provides a method which is gentle on proteins, so that the bikunin plasma fraction obtained contains largely native, bound bikunin or native inter-alpha-trypsin inhibitor.
  • the activity obtained based on inter-alpha-trypsin inhibitor protein, measured as antigen is quite comparable to the activity in human plasma.
  • the plasma fraction according to the invention therefore preferably contains bikunin-containing proteins, such as inter-alpha-trypsin inhibitor, which are at least 80% active, preferably at least 90%. Most preferably the ratio of activity to antigen is about the same.
  • the molecular exclusion chromatography used in the production process according to the invention is a prerequisite for the characterization of the molecular weight of the proteins contained.
  • a preferred plasma fraction essentially contains proteins with an apparent molecular weight in the range from 100 kDa to 500 kDa, preferably 100 to 250 kDa, and should not contain any further essential components.
  • the apparent molecular weight is determined by molecular exclusion chromatography using standard proteins with a certain molecular weight as reference material.
  • the proteins of the l ⁇ l family predominantly contained in the plasma fraction according to the invention are the inter-alpha-trypsin inhibitor itself and preferably at least one further high-molecular protein containing bikunin, that is to say with an apparent molecular weight of at least 100 kDa like the pre-alpha inhibitor.
  • a highly purified I ⁇ l preparation can also be readily obtained by the method according to the invention, the resulting plasma fraction or I ⁇ l preparation according to the invention containing no further bikunin-containing constituent, in particular being essentially free of separate bikunin.
  • “Substantially free” here means less than 10%, preferably less than 5%, based on the total protein.
  • the bikunin plasma fraction is used as the basis for a pharmaceutical preparation.
  • This can be obtained by further purification of the Bikunin proteins and by formulation, measures for sterilization or sterile filtration and inactivation of any pathogens that may be present.
  • the pharmaceutical preparation is preferably provided as a lyophilisate, for example formulated with stabilizing polyols, sugar, sugar alcohols, amino acids or inorganic salts, which formulation is suitable for intravenous administration.
  • the pharmaceutical use of plasma products carries a risk of transmission of pathogens which may be present in the starting plasma, e.g. of blood-borne viruses. These include the hepatitis viruses A, B, C, the HI viruses and parvovirus.
  • pathogens which may be present in the starting plasma
  • these include the hepatitis viruses A, B, C, the HI viruses and parvovirus.
  • various measures are therefore taken in the production of the plasma derivatives to reduce any viruses that may be present by inactivating or depleting or removing them.
  • heat treatment in aqueous solution or in the lyophilisate is used, the heating being preferably carried out in the cleaned product ("bulk") or in the final container.
  • Stabilizers such as inorganic salts, sugars, sugar alcohols, polyols in general or amino acids can have an advantageous effect on maintaining bikunin activity.
  • TNBP trin-butyl phosphate
  • surfactants such as Triton, Tween, Cholat, and the like
  • Other methods see different chemicals, such as Thiocyanates, monochloroacetic acid or organic acids. Alcohols also have a virus-inactivating effect.
  • Nanofiltration is particularly suitable for the depletion or removal of viruses, for example in cross-flow (tangential flow) or in the "dead-end” (Flow) method.
  • the filter materials used for this are on the one hand membranes or depth filters or ultrafilters.
  • filters with a pore size in the range from 15 to 30 nm are used.
  • the therapeutic applicability of the plasma fraction or pharmaceutical preparation according to the invention is initially tested in suitable animal models.
  • a recognized model was, for example, a rat model of polymicrobial sepsis (see Yang S. et al, Am. J-Physiol 277, H1036-H1044 (1999) and Wang P, et al, J-Surg. Res. 85, 59- 65 (1999)).
  • the bikunin plasma fraction according to the invention with a dose of, for example, 30 mg / kg significantly reduced the mortality of the animals.
  • the therapeutic dose is assumed to be in the range of 3 to 300 mg / kg, depending on the degree of sepsis and the time of administration.
  • bikunin plasma fraction or the pharmaceutical preparation especially those consisting essentially of the proteins which have an apparent molecular weight of 100 to 500 kDa or also verified by methods other than gel permeation, for the treatment of septic conditions , comprising severe inflammatory processes in the context of sepsis or septic shock, is therefore another promising subject of the invention.
  • Plasma cryoprecipitate was treated with TNBP and Triton to inactivate viruses.
  • the mixture was then separated using the anion exchanger EMD-TMAE-Sephadex, a tentacle gel, a fraction containing factor VIII and the vWF being obtained.
  • This fraction was further separated using molecular exclusion chromatography on Superose 6 (Pharmacia).
  • the high molecular fraction vWF containing and the FVIII / vWF complex was separated and the fraction containing molecules with the apparent molecular weight in the range of 100 to 500 kDa was obtained.
  • a mouse monoclonal antibody Mab 69.31 produced on the basis of a purified plasma fraction from Example 1, with an inhibiting action against bikunin activity, was produced and selected using conventional methods. This antibody was immobilized on a support suitable for immunoaffinity chromatography.
  • a Bikunin plasma fraction could thus be isolated from the following sources: human plasma, plasma cryoprecipitate, plasma cryoprecipitate purified by ion exchanger and the Bikunin plasma fraction from Example 1 to obtain a further purified fraction.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Rheumatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un procédé de fabrication d'une fraction de plasma à teneur en bikunine, à activité antitrypsine, caractérisé en ce qu'une source renfermant la fraction de plasma à teneur en bikunine est séparée en ses composants par chromatographie par exclusion moléculaire, et en ce qu'une fraction à activité antitrypsine est recueillie.
EP01986698A 2000-10-13 2001-10-11 Fraction de plasma renfermant de la bikunine, son procede de fabrication et son utilisation Withdrawn EP1326893A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10050665 2000-10-13
DE10050665 2000-10-13
PCT/EP2001/011994 WO2002030983A2 (fr) 2000-10-13 2001-10-11 Fraction de plasma renfermant de la bikunine, son procede de fabrication et son utilisation

Publications (1)

Publication Number Publication Date
EP1326893A2 true EP1326893A2 (fr) 2003-07-16

Family

ID=7659599

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Application Number Title Priority Date Filing Date
EP01986698A Withdrawn EP1326893A2 (fr) 2000-10-13 2001-10-11 Fraction de plasma renfermant de la bikunine, son procede de fabrication et son utilisation

Country Status (5)

Country Link
US (1) US20030190732A1 (fr)
EP (1) EP1326893A2 (fr)
JP (1) JP2004511492A (fr)
AU (1) AU2002216968A1 (fr)
WO (1) WO2002030983A2 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7419665B2 (en) * 2003-10-16 2008-09-02 Siemens Healthcare Diagnostics Inc. Monoclonal antibodies for detection of urinary trypsin inhibitors
EP3087991A1 (fr) * 2003-11-08 2016-11-02 Prothera Biologics Composition de protéines d'inhibiteur inter-alpha à partir du plasma pour sa utilisation thérapeutique
CN103142650B (zh) * 2004-11-05 2016-05-11 普罗瑟拉生物公司 治疗用途的来自人血浆的内-α抑制剂蛋白质的制备和组合物
CN101160133B (zh) * 2004-11-05 2013-01-09 普罗瑟拉生物公司 治疗用途的来自人血浆的内-α抑制剂蛋白质的制备和组合物
FR2894145B1 (fr) * 2005-12-07 2008-10-17 Lab Francais Du Fractionnement Utilisation de facteur h du complement a titre de medicament
BR122020017577B1 (pt) 2008-05-28 2021-10-26 Prothera Biologics, Inc Método para purificar proteínas inibidoras inter-alfa
WO2011150284A2 (fr) 2010-05-26 2011-12-01 Baxter International Inc. Élimination de sérine protéases par traitement avec du dioxyde de silicium finement divisé
AU2010202125B1 (en) 2010-05-26 2010-09-02 Takeda Pharmaceutical Company Limited A method to produce an immunoglobulin preparation with improved yield
WO2012012773A1 (fr) 2010-07-23 2012-01-26 Baxter International Inc. Élaboration de protéines de la famille de l'inhibiteur inter-alpha (iaip) à partir du plasma
WO2014039987A2 (fr) 2012-09-09 2014-03-13 Prothera Biologics, Inc. Traitement d'une maladie à l'aide de protéines inter-alpha inhibiteur
US20140206844A1 (en) * 2013-01-18 2014-07-24 Prothera Biologics Methods for isolating blood products from an inter-alpha inhibitor protein-depleted blood product material
WO2022104282A1 (fr) 2020-11-16 2022-05-19 Prothera Biologics, Inc. Procédés de purification de protéines d'inhibiteur inter-alpha

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
US5846763A (en) * 1991-01-14 1998-12-08 New York University DNA encoding tumor necrosis factor stimulated gene 6 (TSG-6)
FR2711371B1 (fr) * 1993-10-18 1995-12-29 Aetsrn Procédé de préparation d'un concentré d'inter-alpha-trypsine inhibiteur à usage thérapeutique et concentré obtenu.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0230983A2 *

Also Published As

Publication number Publication date
AU2002216968A1 (en) 2002-04-22
WO2002030983A2 (fr) 2002-04-18
US20030190732A1 (en) 2003-10-09
JP2004511492A (ja) 2004-04-15
WO2002030983A3 (fr) 2002-12-12

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