WO2010059232A1 - Inactivation de virus par l’arginine - Google Patents

Inactivation de virus par l’arginine Download PDF

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Publication number
WO2010059232A1
WO2010059232A1 PCT/US2009/006221 US2009006221W WO2010059232A1 WO 2010059232 A1 WO2010059232 A1 WO 2010059232A1 US 2009006221 W US2009006221 W US 2009006221W WO 2010059232 A1 WO2010059232 A1 WO 2010059232A1
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Prior art keywords
arginine
virus
factor
inactivation
inactivating
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PCT/US2009/006221
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English (en)
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Keith Selvitelli
Justin Mccue
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Biogen Idec Ma Inc.
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41667218&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010059232(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Biogen Idec Ma Inc. filed Critical Biogen Idec Ma Inc.
Priority to JP2011537425A priority Critical patent/JP5730211B2/ja
Priority to CA2742817A priority patent/CA2742817A1/fr
Priority to DK09761053.9T priority patent/DK2350271T3/en
Priority to EP09761053.9A priority patent/EP2350271B1/fr
Priority to US13/130,540 priority patent/US8980610B2/en
Publication of WO2010059232A1 publication Critical patent/WO2010059232A1/fr
Priority to IL212709A priority patent/IL212709A/en
Priority to US14/659,409 priority patent/US20160010063A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • C12N7/04—Inactivation or attenuation; Producing viral sub-units
    • C12N7/06—Inactivation or attenuation by chemical treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/245—Herpetoviridae, e.g. herpes simplex virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16061—Methods of inactivation or attenuation
    • C12N2710/16063—Methods of inactivation or attenuation by chemical treatment
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16711—Varicellovirus, e.g. human herpesvirus 3, Varicella Zoster, pseudorabies
    • C12N2710/16761—Methods of inactivation or attenuation
    • C12N2710/16763—Methods of inactivation or attenuation by chemical treatment
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/13011—Gammaretrovirus, e.g. murine leukeamia virus
    • C12N2740/13061—Methods of inactivation or attenuation
    • C12N2740/13063—Methods of inactivation or attenuation by chemical treatment

Definitions

  • the present invention relates to inactivation of viruses or reduction of infectious virus titers. More specifically, the invention relates to inactivation or reduction of infectious virus titers by treatment with arginine or salts thereof. The invention also relates to inactivation or reduction of infectious virus titers as a component of therapeutic product preparation and purification regimens.
  • the method described in EP 0131740 Bl consists of contacting the composition containing labile protein with an effective amount of a dialkyl or trialkyl phosphate for a period of time sufficient to render the composition containing labile protein free of lipid-containing viruses.
  • US Patent No. 6,528,246 B2 describes a method for inactivation of viruses using combinations of tri-n-butyl phosphate and Tween, or sodium cholate/TNBP (tri-n-butyl phosphate) and other buffers, detergents and/or surfactants, but requires the use of high concentrations of auxiliary agents such as saccharose and also heat inactivation in the range of 55°C to 67°C which can denature certain proteins and lead to degradation resulting in loss of product.
  • auxiliary agents such as saccharose and also heat inactivation in the range of 55°C to 67°C which can denature certain proteins and lead to degradation resulting in loss of product.
  • WO 94/26287 the inventors recovered 95% of albumin, but obtained a product comprising 250 ppm TRITON X-100 and 35 ppm TNBP. Especially when producing medical preparations, TRITON X-100 concentrations above 50 ppm, or even above 10 ppm are preferably avoided, and it is generally desirable to reduce the detergent content as much as possible. Additionally, some therapeutic proteins are inactivated by TRITON X-100 and, thus, this method for virus inactivation is not optimal for many protein products. [0008] Accordingly, there is a need in the art to inexpensively and safely inactivate or reduce infectious virus titers while preserving the integrity, biological, and/or therapeutic activity of the protein product.
  • Arginine is unique among naturally occurring amino acids in that it has been found to prevent protein aggregation and suppress protein interactions without substantially altering protein conformation. Given these attributes, 0.1M to IM arginine has been used to facilitate refolding of recombinant proteins solubilized from inclusion bodies and 0.5 to 2M arginine has been used to extract active, folded proteins from insoluble pelleted material expressed as a recombinant product in E. coli. (Tsumoto et al, Biotechnology., 20, 1301- 1308 (2004); Ishibashi et al, Protein Expression and Purification, 42, 1-6 (2005); Arakawa et al, Biophysical Chemistry, 127, 1-8 (2008)).
  • Arginine has also been used to enhance recovery of proteins from various types of chromatographic media such as in Protein- A, gel permeation, and dye-affinity chromatography. (Arakawa et al, Protein Expression and Purification, 54, 110-116 (2007); Ejima et al, Analytical Biochemistry, 345, 250-257 (2005)). Arginine has also been used as one component in protein stabilizing formulations, for example, to protect proteins from being inactivated during heat treatment procedures. (Miyano, et al, U.S. Patent No. 5,116,950, issued May 26, 1992).
  • Kozloff et al. have observed that use of 0.2M arginine irreversibly inactivated preparations of some T-even strains of bacteriophage (T2L, a non-enveloped virus). Kozloff et al. also found that this virus specific inactivation was most effective at 30°C and in a pH range of 6.5 to 8.25, and could be accomplished with arginine at 0.033 to 0.2M. However, arginine inactivation of T2L was increasingly ineffective at concentrations of above 0.4 M. Kozloff et al. also observed that arginine did not inactivate T-odd strains of bacteriophage.
  • Yamasaki et al. have observed that at a low (acidic) pH and at low temperatures (samples on ice), arginine can inactivate the enveloped herpes simplex virus type-1 (HSV-I) and influenza virus. However, at more neutral pH levels ⁇ i.e., pH 5.0-pH 7.0), Yamasaki et al found arginine to be ineffective at inactivating these viruses. Yamasaki et al. also found that arginine was ineffective at inactivating non-enveloped polio virus. (Yamaski et al, Journal of Pharmaceutical Sciences, (Jan. 10, 2008) 97(8), 3067-3073 ).
  • the present invention allows the use of high concentrations of arginine to effectively inactivate or reduce infectious titers of lipid coated (enveloped) viruses that may be present during the production of a biological product, such as a monoclonal antibody or other therapeutic protein.
  • virus inactivation or reduction of infectious virus titers occurs in a neutral (pH ⁇ 7) environment.
  • virus inactivation or reduction of infectious virus titers occurs at temperatures ranging from 2° to 42 0 C.
  • the present invention provides a component in a process of obtaining a protein preparation purified to a degree suitable for administration, preferably as therapeutically useful compound, to a living subject.
  • a protein preparation purified to a degree suitable for administration, preferably as therapeutically useful compound, to a living subject.
  • the present invention may be used as part of the process in preparing therapeutically useful proteins such as factor VIII, factor IX, fibrinogen, gamma-globulin, antibodies and antibody fragments.
  • the present invention may be used to inactivate or reduce infectious virus titers of enveloped viruses such as a mammalian or avian Leukemia virus, Herpes virus, Pox virus, Hepadnavirus, Flavivirus, Togavirus, Coronavirus, Hepatitis virus, Retrovirus, Orthomyxovirus, Paramyxovirus, Rhadovirus, Bunyavirus, Filovirus, and Reovirus.
  • infectious virus titers of enveloped viruses such as a mammalian or avian Leukemia virus, Herpes virus, Pox virus, Hepadnavirus, Flavivirus, Togavirus, Coronavirus, Hepatitis virus, Retrovirus, Orthomyxovirus, Paramyxovirus, Rhadovirus, Bunyavirus, Filovirus, and Reovirus.
  • Figure 1 depicts the kinetics of X-MLV inactivation by 0.10% TRITON ® X-100.
  • Figure 2 depicts the kinetics of X-MLV inactivation by 0.20% TRITON ® X-100.
  • Figure 3 depicts the kinetics of X-MLV inactivation for Fc ⁇ -Fc ⁇ (BIIB-016) at pH
  • Figure 4 depicts the kinetics of X-MLV inactivation for Fc ⁇ -Fc ⁇ (BIIB-016) at pH
  • Figure 5 depicts the kinetics of X-MLV inactivation for Fc ⁇ -Fc ⁇ (BIIB-016) at neutral pH in 1 M arginine.
  • LC 0 Load Control (Time 0).
  • Figure 6 depicts kinetics of X-MLV inactivation for Fc ⁇ -Fc ⁇ (BID3-016) at neutral pH in 1 M arginine with Fc ⁇ -Fc ⁇ .
  • LC 0 Load Control (Time 0).
  • Figure 7 depicts kinetics of X-MLV inactivation using: (a). 0.1 M arginine, (b). 0.5
  • Figure 8 depicts the kinetics of SuHV-I inactivation using 1.0 M arginine buffer.
  • Figure 9 depicts the kinetics of MMV inactivation using 1.0 M arginine buffer.
  • Figure 10 depicts kinetics of X-MLV inactivation using 1.0 M arginine buffer and
  • Figure 11 depicts kinetics of SuHVl inactivation using 1.0 M arginine buffer
  • Figure 12 depicts kinetics of X-MLV inactivation using 1.0 M glycine buffer.
  • Figure 13 depicts a process flow chart for purification of proteins and arginine inactivation of viruses.
  • Figure 14 depicts percentage of GE2 protein monomer remaining over a 24-hour incubation period at low pH (3.7) or high arginine concentration (1.0 M) as compared to a control solution.
  • Figure 15 depicts percentage of Lingo protein monomer remaining over a 24-hour incubation period at low pH (3.7) or high arginine concentration (1.0 M) as compared to a control solution.
  • Figure 16 depicts high-molecular weight protein aggregation over a 24-hour incubation period of GE2 protein at low pH (3.7) or high arginine concentration (1.0 M) as compared to a control solution.
  • the arrow points to formation of high-molecular weight species.
  • Figure 17 depicts percentage of FIX protein monomer remaining over a 24-hour incubation period following bolus addition of arginine to a final concentration of 0.5 M or
  • wash solution refers to the solution used to separate contaminant(s), such as process-related impurities, from a target protein and a stationary phase culture such as a Size Exclusion Chromatography (SEC), Ion Exchange Chromatography (LEC), affinity chromatography or other chromatographic medium.
  • SEC Size Exclusion Chromatography
  • LEC Ion Exchange Chromatography
  • affinity chromatography affinity chromatography or other chromatographic medium.
  • the wash solution may comprise a buffer, a detergent, a solvent, a polymer, or any combination thereof, hi some embodiments, the wash solution may comprise about 0.1M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 1.1 M, 1.2 M, 1.3 M, 1.4 M, 1.5 M, 1.6 M, 1.7 M, 1.8 M, 1.9 M, 2 M, 2.5 M, or 3.0 M arginine or salt thereof.
  • buffer refers to a solution that resists changes in pH by the action of its acid-base conjugate components.
  • the term "elution reagent” refers to a reagent used to elute or dissociate a therapeutic protein from a stationary phase culture such as an SEC, IEC, affinity or other chromatographic medium.
  • the elution reagent may comprise a buffer, a salt, a detergent, a solvent, a polymer, a glycol compound or any combination thereof.
  • Examples of "glycols" useful in the methods of the invention include, without limitation, ethylene glycol, propylene glycol, hexylene glycol, polyethylene glycol, or polypropylene glycol.
  • process-related impurities refers to any undesirable component in a biological preparation such as viruses, nucleotides, polynucleotides, non-target proteins (such as host cell proteins, HCP), other cellular components (such as lipids and glycolipids), and any other contaminants that arise from, or during, production, separation, and/or purification processes.
  • the term "recombinantly produced,” when used in reference to a protein, refers to that protein produced using recombinant DNA technology.
  • the recombinantly produced protein is produced by a mammalian cell.
  • the cell is a human cell.
  • the cell is a non-human cell such as Chinese Hamster Ovary (CHO) cell or Baby Hamster Kidney (BHK) cell.
  • the cell type can be any suitable cell for producing recombinant proteins according to methods of the invention.
  • fusion protein when used in reference to polypeptides such as an “Fc fusion” protein, refers to polypeptides comprising amino acid sequences derived from two or more heterologous polypeptides, such as portions of proteins which are encoded by separate genes (whether the genes occur in the same or in a different species of organism), or wherein a fusion protein refers to a polypeptide comprising a portion of a naturally occurring gene (or a derivative or variant thereof) covalently linked with an artificial or non-naturally occurring peptide or polypeptide.
  • the term "inactivate” or other forms of this word when used in reference to viruses is intended to indicate not only complete virus inactivation (i.e., no detectable infectious virus) but also the detectable reducing or reduction of infectious virus titers (i.e., lowering or lowered levels of detectable infectious virus).
  • the reducing or reduction of infectious virus titers is included within the meaning of "virus inactivation” (and other forms of this term) whether or not such reducing or reduction is explicitly stated herein.
  • Therapeutic protein preparations may include recombinant or non-recombinant proteins.
  • non-recombinant proteins include proteins isolated from whole blood, blood plasma, plasma concentrate, precipitates from any fraction of blood plasma, supernatant from any fractioning of blood plasma, serum, cryoprecipitates, cell lysates, or similar sources.
  • Therapeutic proteins prepared according to the present invention includes any therapeutically useful peptide, polypeptide, glycopeptide, or protein.
  • Fc region refers to a C-terminal region of an IgG heavy chain, hi a particular embodiment, the Fc region refers to the C-terminal region of a human IgG heavy chain. Although the boundaries of the Fc region of an IgG heavy chain might vary slightly, the human IgG heavy chain Fc region is usually defined to span from the amino acid residue at position Cys 226 of the native polypeptide to the carboxyl-terminus.
  • the term "mass concentration,” when used in reference to the removal of process-related impurities, refers to a ratio of the mass of process-related impurities to the mass of therapeutic protein.
  • the ratio may be calculated as nanograms of process-related impurities per milligram of therapeutic protein when the mass concentration is parts per million (ppm), and the ratio may be calculated as picograms of process-related impurities per milligram of therapeutic protein when the mass concentration is parts per billion (ppb).
  • percent recovery and “percent purity,” are intended to mean the recovery or purity achieved when a target compound (e.g. , a protein) is conveyed through a purification step or procedure, compared to the quantity or purity of the target compound in the sample prior to the purification step or procedure. Achieving an increase in percent purity entails obtaining a product with reduced levels of contaminants (in proportion to the target compound) when a sample is compared before and after a purification step or procedure.
  • a target compound e.g. , a protein
  • Preferred percentages within the meaning of percent recovery and percent purity as defined above include, without limitation, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.
  • the present invention provides methods of inactivating a virus comprising contacting the virus with a solution comprising at least about 0.2 M arginine, wherein the solution is at a pH above about 5.0 and wherein the virus is not a bacteriophage or other non-enveloped virus.
  • the present invention relates to a method of reducing the titer of infectious virus in a therapeutic protein preparation comprising exposing the therapeutic protein preparation to a solution having a final concentration of at least about
  • the therapeutic protein is a recombinant protein.
  • the recombinant protein may be an immunoglobulin (antibody) or fragment thereof.
  • the protein preparation may comprise a blood coagulation factor.
  • the blood coagulation factor of the present invention can be a blood coagulation factor such as, but without limitation, Factor-I (fibrinogen), Factor-II (prothrombin), Tissue factor, Factor-V (proaccelerin, labile factor), Factor- VI, Factor- VII (stable factor), Factor-
  • therapeutic proteins prepared by methods of the present invention are produced by eukaryotic cells.
  • the eukaryotic cells of the invention are mammalian cells.
  • the mammalian cells are Chinese Hamster Ovary (CHO) cells or Baby Hamster Kidney (BHK) cells.
  • the mammalian cells are human cells.
  • the cells are multi-hybrid (2 or more cells) fused together (e.g., mouse or human hybridoma cells).
  • the arginine viral inactivation method of the present invention may be performed prior to any purification procedure (for example, a chromatographic procedure), during or between one or more purification procedures, and/or after all purification procedures.
  • the invention comprises proteins produced by methods of the present invention.
  • the chromatography steps of the present invention may employ any type of chromatographic method.
  • Such chromatography methods include, for example but without limitation: gas chromatography, liquid chromatography (e.g., high performance liquid chromatography); affinity chromatography (such as Protein-A or antibody-antigen affinity chromatography); supercritical fluid chromatography; ion exchange chromatography (such as anion or cation exchange chromatography); size-exclusion chromatography; reversed phase chromatography; two-dimensional chromatography; simulated moving bed chromatography, pyrolysis gas chromatography, fast protein (FPLC) chromatography; countercurrent chromatography; chiral chromatography; aqueous normal phase (ANP) chromatography; mixed mode chromatography; and, pseudo-affinity chromatography.
  • gas chromatography liquid chromatography
  • affinity chromatography such as Protein-A or antibody-antigen affinity chromatography
  • supercritical fluid chromatography such as ion exchange chromatography (such as anion or cation exchange
  • the pH range used in the arginine inactivation steps of the present invention can be above or about 5.0, above or about 5.5, above or about 6.0, above or about 6.5, above or about 7.0, above or about 8.0, above or about 9.0.
  • the arginine inactivation step is carried out at a pH range from about 5.0 to about 9.0.
  • the pH range is from about 6.0 to about 8.5.
  • the pH range is about 6.5 to about 7.5.
  • the pH is about 7.0.
  • the arginine concentration is about 0.1M, 0.2M, 0.3M, 0.4M, 0.5 M, 0.6M, 0.7M, 0.8M, 0.9M, 1 M, 1.5 M, 2 M, 2.5M, or about 3 M.
  • the viral inactivation methods of the present invention take place at an arginine concentration of about 0.2 M to about 3 M.
  • the arginine concentration is within a range of about 0.5 M to about 3 M.
  • the arginine concentration is within a range of about 1 M to about 3 M.
  • the arginine concentration is within a range of about 1 M to about 2 M.
  • arginine refers to arginine and salts thereof.
  • virus inactivation via use of arginine is carried out at temperatures of about O 0 C to about 55 0 C; including for example temperature ranges of about O 0 C to about 4°C, about O 0 C to 8 0 C, about O 0 C to about 12°C, about O 0 C to about 18 0 C, about O 0 C to about 2O 0 C, about O 0 C to about 25 0 C, about O 0 C to about 37 0 C, about O 0 C to about 40 0 C, about O 0 C to about 42 0 C, about 2 0 C to about 4°C, about 2 0 C to about 8°C, about 2 0 C to about 12 0 C, about 2°C to about 18 0 C, about 2 0 C to about 2O 0 C, about 2 0 C to about 25 0 C, about 2°C to about 37 0 C, about 2 0 C to about 4O 0 C, about 2 0 C to about 42 0 C
  • virus inactivation via use of arginine is carried out at temperatures of O 0 C to 55 0 C; including for example temperature ranges of 0 to 4°C, 0 to 8 0 C, 0 to 12 0 C, 0 to 18°C, 0 to 2O 0 C, 0 to 25 0 C, 0 to 37 0 C, 0 to 4O 0 C, 0 to 42 0 C, 2 to 4°C, 2 to 8 0 C, 2 to 12°C, 2 to 18°C, 2 to 20 0 C, 2 to 25 0 C, 2 to 37°C, 2 to 4O 0 C, 2 to 42 0 C, 2 to 55°C, 4 to 8 0 C, 4 to 12 0 C, 4 to 18 0 C, 4 to 25 0 C, 4 to 37 0 C, 4 to 4O 0 C, 4 to 42 0 C, 4 to 55 0 C, 8 to 12 0 C, 4 to 18 0 C, 4 to 25 0 C, 4 to 37
  • the present invention includes inactivation of viruses as a component of a therapeutic product (or drug substance) preparation regimen wherein virus inactivation is accomplished by contacting a therapeutic product, or composition containing a therapeutic product, with arginine.
  • virus is contacted in a solution with a final arginine concentration of about 0.1M or greater.
  • the final arginine concentration is about 0.5M or greater or about 1.0M or greater.
  • virus inactivation is accomplished in a solution with arginine wherein the solution is at a pH value which is neutral (about pH 7) or near neutral (about pH 6 to about pH 8.5).
  • the neutral or near neutral pH value is about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, and about 8.5.
  • hi one embodiment virus inactivation with arginine is performed before any prior therapeutic product purification steps or procedures.
  • virus inactivation is performed as part of a cell culture harvest procedure.
  • virus inactivation is performed after a cell culture harvest procedure
  • hi one embodiment virus inactivation is performed as part of a cell culture supernatant clarification procedure.
  • virus inactivation is performed after a cell culture supernatant clarification procedure.
  • virus inactivation is performed during (as part of), or in between, therapeutic product purification steps or procedures
  • hi one embodiment virus inactivation is performed after one or more therapeutic product purification steps or procedures.
  • virus inactivation is performed after one or more therapeutic product purification steps comprising use of chromatography. In one embodiment virus inactivation is performed after one or more therapeutic product purification steps comprising use of affinity chromatography, such as Protein-A or Protein-G chromatography (or chromatography with Protein-A or Protein-G derivatives or analogs). In one embodiment virus inactivation is performed between chromatography purification steps or procedures. In one embodiment virus inactivation is performed prior to a virus filtration step or procedure.
  • virus inactivation is performed after a virus filtration step or procedure, hi one embodiment virus inactivation is performed after a chromatography purification step or procedure and before a virus filtration step or procedure, hi one embodiment virus inactivation is performed prior to an ultrafiltration or diafiltration step or procedure. In one embodiment virus inactivation is performed after an ultrafiltration or diafiltration step or procedure. In one embodiment virus inactivation is performed after a virus filtration step or procedure and prior to an ultrafiltration or diafiltration step or procedure. In one embodiment virus inactivation is performed after all therapeutic product purification steps or procedures and prior to final therapeutic product formulation. In one embodiment virus inactivation is performed as part of a final therapeutic product formulation process.
  • Viruses that may be inactivated by embodiments of the present invention include, without limitation, enveloped viruses classified such as, for example, mammalian or avian Leukemia viruses, Herpes viruses, Pox viruses, Hepadnaviruses, Flaviviruses, Togaviruses, Coronaviruses, Hepatitis viruses, Retroviruses, Orthomyxoviruses, Paramyxoviruses, Rhadoviruses, Bunyaviruses, Filoviruses, and Reoviruses.
  • enveloped viruses classified such as, for example, mammalian or avian Leukemia viruses, Herpes viruses, Pox viruses, Hepadnaviruses, Flaviviruses, Togaviruses, Coronaviruses, Hepatitis viruses, Retroviruses, Orthomyxoviruses, Paramyxoviruses, Rhadoviruses, Bunyaviruses, Filoviruses, and Reoviruses.
  • Exemplary viruses tested include: a) Xenotropic Murine leukemia virus (X-MLV), a model endogenous retrovirus (enveloped, RNA genome virus) potentially present in cell culture harvests of Chinese Hamster Ovary cells (CHO) (a cell line commonly used to produce recombinant proteins); b) Murine minute virus (MMV) as a model adventitious virus (non-enveloped, DNA genome) potentially introduced during protein production/processing; and c) Suid herpesvirus 1 (SuHV-I) as a model enveloped, DNA containing virus with moderate resistance to physical/chemical inactivation.
  • X-MLV Xenotropic Murine leukemia virus
  • CHO Chinese Hamster Ovary cells
  • MMV Murine minute virus
  • Suid herpesvirus 1 Suid herpesvirus 1
  • Virus inactivation kinetics obtained by exposure to low pH, TRITON X-100 and arginine were studied using sample process intermediates of a recombinant antibody designated GE2-Fc ⁇ -Fc ⁇ .
  • the process intermediates used in these inactivation studies are shown in Table 1. All studies were performed at 2-8 0 C.
  • TRITON ® X- 100 was added to the GE2-Fc ⁇ -Fc ⁇ clarified conditioned media (CCM) at concentrations of 0.10% (v/v) and 0.20% (v/v).
  • MABSELECTTM GE Healthcare Bio-Sciences Corp., Piscataway, NJ, USA
  • Protein- A chromatography eluates containing GE2-Fc ⁇ -Fc ⁇ with the pH adjusted to 3.7 or 3.9 were used as the starting material for the low pH viral inactivation studies.
  • Neutralized MABSELECTTM Eluate buffer (1.0 M arginine-HCl, ⁇ 5 rnM Tris, pH 7.3 (+/-) 0.5) and neutralized MABSELECTTM Eluate buffer containing GE2-Fc ⁇ -Fc ⁇ were also used as process intermediates for the additional inactivation studies. The process intermediates used in these studies were known to be stable under the examined conditions.
  • TRITON ® X-100 inactivation experiments were performed in duplicate using final concentrations of 0.10% or 0.20% (v/v) TRITON ® X-100 in GE2-Fc ⁇ -Fc ⁇ clarified conditioned media. Table 2 shows parameters in four experiments performed in these studies.
  • Tables 3 and 4 summarize X-MLV Reduction Factors (RF) at various time points, while Table 13 summarizes the RF values for the four runs after 120 min exposure to TRITON X-100.
  • Figures 1 and 2 show the X-MLV titer as a function of time for 0.10% and 0.20% TRITON ® X-100 addition, respectively.
  • Input volume output volume. Final quenched volume of each sample was 20ml. e Not applicable.
  • a "Hold Control” is a sample that is not exposed to the virus inactivation process, and represents what the virus level would be if an inactivation process was not used.
  • the "Hold Control” sample is held for the same time and temperature as the test article. Thus, any loss in virus titer measured in the hold control (which is not expected) would be due to events other than the inactivation process.
  • **Quenching indicates dilution or changing virus inactivation sample conditions into non- inactivation conditions.
  • quenching Tween inactivation conditions is done by diluting a sample containing Tween to a Tween concentration less than the critical level required for micelle formation, thereby nullifying the ability of Tween to inactivate virus.
  • low pH virus inactivation conditions are quenched by increasing the pH to neutral or near neutral levels.
  • Test Article is the protein solution which is being evaluated for Virus inactivation.
  • a "Spiked” Test Article is one in which virus has been added (“spiked into”) to the solution.
  • X-MLV inactivation data for GE2-Fc ⁇ -Fc ⁇ samples exposed to 0.20% TRITON® X-100 a Titer obtained from TCID 5O assay.
  • Dilution factor 20 (from quenching 1 mL of spiked TA with 19 mL of media).
  • d RF logio (Input virus titer per mL) x Input volume
  • Input volume output volume. Final quenched volume of each sample was 20ml. e Not applicable.
  • Table 5 shows parameters in low pH virus inactivation studies. Experiments were performed in duplicate. Table 5 Parameters in Low pH Inactivation Studies
  • Tables 6 and 7 summarize X-MLV Reduction Factors (RF) at various time points, while Table 13 summarizes RF values following 120 min. of exposure at low pH conditions.
  • Figures 3 and 4 show inactivation kinetics of X-MLV for pH 3.7 and 3.9, respectively.
  • X-MLV was detectable in one of the runs at pH 3.7 for several time points (Run #5), but within assay variability ( ⁇ 1 logio) of the duplicate run (Run #6), which was below detection for all time points > 5 minutes.
  • Input volume volume of collected sample.
  • Output volume volume of neutralized sample.
  • Virus Control titers were used for the Input virus titers due to low virus titers in the Load and Hold controls, indicating that the neutralized TA material had a virucidal effect. d Not applicable.
  • Input volume volume of collected sample.
  • Virus Control titers were used for the Input virus titers due to low virus titers in the Load and Hold controls, indicating that the neutralized TA material had a virucidal effect. d Not applicable.
  • Tables 11 and 12 summarize X-MLV Reduction Factors (RF) at various time points, while Table 13 summarizes RF values for four runs after 120 min.
  • Figures 5 and 6 show the inactivation kinetics of X-MLV in 1 M arginine buffer, in the absence and presence of GE2-Fc ⁇ -Fc ⁇ , respectively.
  • X-MLV was at, or below, detectable levels following 15 minutes in neutral solution containing 1 M arginine.
  • detectable levels of virus were present after 5 minutes exposure in all of the studies (Runs 9-12).
  • X- MLV inactivation kinetics in the arginine studies were slightly less rapid compared with the inactivation kinetics measured during the low pH studies.
  • X-MLV levels were at, or below, detection following 30 minutes exposure.
  • Output Virus titer represents the last time point (120 minutes) for each study b Calculation:
  • X-MLV was chosen as a model retrovirus for this study as representative of endogenous retroviruses commonly found in mammalian cell culture.
  • the additional model viruses selected for the study comprise a wide range of virus characteristics.
  • the viruses evaluated were xenotropic Murine leukemia virus (X-MLV), Murine minute virus (MMV), and Suid herpesvirus 1 (SuHV-I) (Table 15).
  • MMV was not inactivated in the presence of 1.0 M arginine (Table 14) over a 4 hour period (Table 19).
  • Run 3 Titer obtained from TdD 50 assay.
  • Dilution factor 10 (from quenching 1 mL of spiked TA with 9 mL of media).
  • c Titer of sample, adjusted for the dilution factor. Obtained by multiplying titer from TdD 50 assay and the dilution factor from the quench, if appropriate.
  • d RF logio (Input virus titer per mL)
  • a Titer obtained from TCID 5O assay obtained from TCID 5O assay.
  • Dilution factor 10 (from quenching 1 mL of spiked TA with 9 mL of media).
  • RF logio (Input virus titer per mL)
  • Input volume output volume. Hold control titer was used as input, since the Hold control titer was lower than the Load control titer by > 0.5 logio. e Not applicable.
  • Input volume output volume.
  • the Load control was used as the input for these runs, since the Hold control was completely inactivated. This indicates that the Factor VIII Affinity Resin Eluate Buffer, with or without arginine, inactivates SuHV-I . e Not applicable.
  • N/D Not determined; no sample was collected.
  • Table 23 summarizes the results of the studies, including virus inactivation (Reduction Factor).
  • the enveloped viruses evaluated in the studies (X-MLV and SuHV-I) were inactivated in the presence of l.OM arginine, while the non-enveloped virus (MMV) was not inactivated.
  • MMV non-enveloped virus
  • Use of l.OM glycine did not inactivate X-MLV.
  • the results show use of high concentrations of arginine (1.0M) in a neutral buffer could be useful as an effective virus inactivation method for enveloped viruses.
  • a Output Virus titer represents the last time point (120 or 240 minutes) for each study b Calculation:
  • therapeutic proteins such as fusion proteins and monoclonal antibodies show good product stability in the presence of high concentrations of arginine.
  • methods of inactivating or reducing the infectious titer of a virus comprising contacting the virus with arginine are applied during isolation and/or production of therapeutic proteins.
  • therapeutic proteins include, without limitation, fusion proteins such as Factor IX-Fc (FIX-Fc), as shown above, and additional Fc-fusion proteins such as clotting factor, Factor VII, and Factor VIII-Fc fusion proteins and others, for example, such as those disclosed in U.S. Patent Nos. 7,348,004; 7,381,408; and 7,404,956 and U.S.
  • Therapeutic proteins also include, without limitation, antibodies such as antibodies that bind LINGO-I or antibodies that bind TWEAK receptor (Fnl4), which are disclosed in International Appl. Publ. Nos. WO 2007/008547 and WO 2008/086006 and International Appl. No. PCT/US2009/003999, for Lingo antibodies, or International Appl. No. PCT/US2009/043382 for TWEAK receptor antibodies, each of which are incorporated by reference herein.
  • antibodies such as antibodies that bind LINGO-I or antibodies that bind TWEAK receptor (Fnl4), which are disclosed in International Appl. Publ. Nos. WO 2007/008547 and WO 2008/086006 and International Appl. No. PCT/US2009/003999, for Lingo antibodies, or International Appl. No. PCT/US2009/043382 for TWEAK receptor antibodies, each of which are incorporated by reference herein.
  • Embodiments of the invention (E) include E1-E31 :
  • a method of inactivating or reducing the infectious titer of an enveloped virus comprising contacting said virus with arginine, wherein said contacting occurs in a solution comprising at least about 0.2 M arginine and wherein said solution is at a pH above about 6.0.
  • a method of inactivating or reducing the infectious titer of an enveloped virus contaminating a therapeutic biological product comprising contacting said virus with arginine, wherein said contacting occurs in a solution comprising at least about 0.2 M arginine and wherein said solution is at a pH above about 6.0.
  • E3 The method of El or E2, wherein said pH is selected from the group consisting of: a) pH of about 6.0 to about 8.5; b) pH of about 6.5 to about 8.0; c) pH of about 6.5 to about 7.5; d) pH ofabout 6.0 to 8.0; e) pH of about 7.0 to about 8.0; f) pH of about 7.0 to about 7.5; g) pH of about 6.0; h) pH of about 6.5; i) pH of about 7.0; j) pH of about 7.5; k) pH of about 8.0; and, 1) pH of about 8.5.
  • E6 The method of E5, wherein said glycol compound is present at a concentration of less than or equal to about 50% (weight to volume).
  • E7 The method of E5 or E6, wherein said glycol compound is selected from the group consisting of: a) propylene glycol; b) polypropylene glycol; c) ethylene glycol; d) polyethylene glycol; e) hexylene glycol; and, f) polyhexylene glycol.
  • E8 The method of any one of El to E7, wherein said inactivating or reducing is performed as part of a product purification process.
  • E9. The method of E8, wherein said inactivating or reducing is performed during a cell culture harvest procedure.
  • E12 The method of E8, wherein said inactivating or reducing is performed subsequent to a chromatography purification procedure, wherein said procedure comprises contacting said therapeutic biological product with a chromatographic media.
  • E13 The method of E8, wherein said inactivating or reducing is performed subsequent to one or more chromatography purification procedures but prior to another or more chromatography purification procedures, wherein said procedures comprise contacting said therapeutic biological product with a chromatographic media.
  • E14 The method of E8, wherein said inactivating or reducing is performed subsequent to all chromatography purification procedures used in preparing said biological product.
  • E15 The method of E8, wherein said inactivating or reducing is performed prior to a virus filtration procedure.
  • E 16 The method of E8, wherein said inactivating or reducing is performed subsequent to a virus filtration procedure.
  • E 17 The method of E8, wherein said inactivating or reducing is performed subsequent to a virus filtration procedure and prior to an ultrafiltration or diafiltration procedure.
  • E18 The method of E8, wherein said inactivating or reducing is performed prior to an ultrafiltration or diafiltration procedure.
  • E19 The method of E8, wherein said inactivating or reducing is performed subsequent to an ultrafiltration or diafiltration procedure.
  • E20 The method of any one of El to E19, wherein the therapeutic biological product comprises a recombinant protein.
  • E21 The method of any one of El to El 9, wherein said therapeutic biological product comprises a naturally occurring or recombinant immunoglobulin.
  • said blood coagulation factor is selected from the group consisting of: a) fibrinogen (Factor I); b) fibrin; c) prothrombin (Factor II); d) thrombin; e) anti-thrombin; f) Tissue factor Co-factor of Vila (Factor 111); g) Protein C; h) Protein S; i) protein Z; j) Protein Z-related protease inhibitor; k) heparin cofactor II;
  • E24 The method of any one of El to E22, wherein said biological product is produced by eukaryotic cells.
  • E25 The method of E24, wherein said biological product is produced by mammalian cells.
  • E26 The method of E25, wherein said biological product is produced by
  • E28 The method of E25, wherein said biological product is produced by human cells.
  • E29 The method of any one of El to E28, wherein said therapeutic protein is a fusion protein.
  • E30 The method of E29, wherein said fusion protein is an Fc-fusion protein.
  • E31 The method of E21, wherein said naturally occurring or recombinant immunoglobulin is an antibody that binds LINGO-I or an antibody that binds TWEAK receptor (Fnl4).

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Abstract

La présente invention concerne des procédés d'utilisation de l'arginine pour inactiver ou réduire le titre infectieux de virus à enveloppe potentiellement présents dans des compositions biologiques produites par des cellules eucaryotes (telles que des anticorps ou d'autres protéines thérapeutiques). Dans certains modes de réalisation, l'inactivation ou la réduction de titres viraux par exposition à l'arginine est réalisée dans un environnement neutre (pH ~7) ou proche de la neutralité (~pH 6 à ~pH 8).
PCT/US2009/006221 2008-11-20 2009-11-20 Inactivation de virus par l’arginine WO2010059232A1 (fr)

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JP2011537425A JP5730211B2 (ja) 2008-11-20 2009-11-20 ウイルスのアルギニン不活化
CA2742817A CA2742817A1 (fr) 2008-11-20 2009-11-20 Inactivation de virus par l'arginine
DK09761053.9T DK2350271T3 (en) 2008-11-20 2009-11-20 ARGININ INACTIVATION OF ENVIRONMENT VIRA
EP09761053.9A EP2350271B1 (fr) 2008-11-20 2009-11-20 Inactivation de virus enveloppés par l'arginine
US13/130,540 US8980610B2 (en) 2008-11-20 2009-11-20 Arginine inactivation of viruses
IL212709A IL212709A (en) 2008-11-20 2011-05-05 A method for eliminating or removing the infectious titer of Shell virus
US14/659,409 US20160010063A1 (en) 2008-11-20 2015-03-16 Arginine inactivation of viruses

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