US20030138417A1 - Stable liquid pharmaceutical formulation of IgG antibodies - Google Patents

Stable liquid pharmaceutical formulation of IgG antibodies Download PDF

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US20030138417A1
US20030138417A1 US10/291,528 US29152802A US2003138417A1 US 20030138417 A1 US20030138417 A1 US 20030138417A1 US 29152802 A US29152802 A US 29152802A US 2003138417 A1 US2003138417 A1 US 2003138417A1
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antibody
formulation
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Elizabet Kaisheva
Supriya Gupta
Shanti Duvur
Malathy Subramanian
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AbbVie Biotherapeutics Inc
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Protein Design Labs Inc
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Assigned to PROTEIN DESIGN LABS, INC. reassignment PROTEIN DESIGN LABS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DUVUR, SHANTI G., GUPTA, SUPRIYA, KAISHEVA, ELIZABET A., SUBRAMANIAN, MALATHY
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249Interferons
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591Stabilisation, fragmentation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244Interleukins [IL]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244Interleukins [IL]
    • C07K16/246IL-2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C07K16/2854Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72 against selectins, e.g. CD62
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

This invention is directed to a stable liquid pharmaceutical formulation comprising a high concentration, e.g. 50 mg/ml or more, of antibody in about 20-60 mM succinate buffer or 30-70 mM histidine buffer, having pH from about pH 5.5 to about pH 6.5, about 0.01-0.1% polysorbate, and a tonicity modifier that contributes to the isotonicity of the formulation. This liquid formulation is stable at refrigerated temperature (2-8° C.) for at least 1 year, and preferably 2 years. This liquid formulation is suitable for subcutaneous injection. The preferred antibodies include Daclizumab, a humanized anti-IL-2 receptor monoclonal antibody; HAIL-12, a humanized anti-IL-12 monoclonal antibody; HuEP5C7, a humanized anti-L selectin monoclonal antibody; and Flintozumab, a humanized anti-gamma interferon monoclonal antibody.

Description

  • This application claims the benefit of U.S. Provisional Application No. 60/337,509 filed Nov. 8, 2001. [0001]
  • FIELD OF THE INVENTION
  • The present invention relates generally to the field of pharmaceutical formulation of antibodies. Specifically, the present invention relates to a stable, liquid, high concentration antibody formulation. This invention is exemplified by a stabilized liquid formulation of Daclizumab, an anti-IL2 receptor antibody; HAIL-12, a humanized anti-IL-12 monoclonal antibody; and HuEP5C7, a humanized anti-L selectin monoclonal antibody. [0002]
  • BACKGROUND OF THE INVENTION
  • Many protein preparations intended for human use require stabilizers to prevent denaturation, aggregation and other alternations to the proteins prior to the use of the preparation. This instability is manifested in the formation of soluble/insoluble particles, and is often increased when the protein preparation is stored over time and during shipping. A major aim in the development of protein drug formulations is to maintain both protein solubility, stability and bioactivity. [0003]
  • Immunoglobulins, in particular, are recognized as possessing characteristics that tend to form aggregates and particulates in solution, and as such, may require filtration before use for intravenous or subcutaneous injection. The formation of protein aggregates and particulates has long been a problem in the development of parenteral immunoglobulin products, especially when the immunoglobulins are formulated at high concentrations. Synagis™ (MedImmune) is a humanized monoclonal IgG1 antibody produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the T protein of respiratory syncytial virus (RSV). Synagis™ is a composite of human (90%) and murine (10%) antibody sequences. Synagis™ is supplied as a sterile lyophilized product for reconstruction with sterile water for injection. Reconstituted Synagis™ is to be administered by intramuscular injection only. Upon reconstitution, Synagis™ contains the following excipients: 47 mM histidine, 3.0 mM glycine, 5.6% mannitol, and the active ingredient, IgG1 antibody, at a concentration of 100 milligrams per vial. The reconstituted Synagis™ is to be administered within 6 hours of reconstitution. [0004]
  • WO 89/11297 discloses a lyophilized monoclonal antibody formulation comprising a lyophilized formulation of 1-25 mg/ml IgG monoclonal antibody, 2-10% maltose, and sodium acetate, phosphate, or citrate buffer having a pH between 3.0 to 6.0. [0005]
  • WO 97/45140 discloses an aqueous preparation of anti-CD4 antibody concentrated to approximately 100 mg/ml in 100 mM sodium citrate, 0.05 mM EDTA, pH 6.0. The application discloses a slight rise in turbidity after concentration of the antibody, which likely reflects protein aggregation. Removing this aggregation requires addition of Polysorbate 80 and sterile filtration. [0006]
  • WO 90/11091 discloses injectable aqueous compositions comprising about 5 mg/ml of IgM, 2.5-5% (w/v) human serum albumin, in 8-20 mM phosphate buffer, 270 mM sodium chloride, pH 6.8-7.4. [0007]
  • U.S. Pat. No. 6,171,586 discloses a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, an acetate buffer from about pH 4.8 to about 5.5, a surfactant, and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride. [0008]
  • U.S. Patent Application Publication No. US 2001/0014326A1 discloses a pre-lyophilized antibody formulation containing 25 mg/ml anti-IgE antibody, 5 mM histidine, pH 6.0, 85 mM sucrose, and 0.01% polysorbate 20. [0009]
  • U.S. Pat. No. 5,744,132 discloses a composition comprising 1-1000 μg/ml IL-12 antibody, 2% sucrose, 4.15% mannitol, 10 mM sodium succinate, and about 0.02% Tween® 20, having a pH of about 5.6. [0010]
  • U.S. Pat. No. 6,267,958 discloses a reconstituted formulation of 100 mg/ml rhuMab E25, in 20 mM histidine, pH 6.0, 340 mM sucrose, 0.04% polysorbate 20, and 0.9% benzyl alcohol. [0011]
  • U.S. Pat. No. 6,165,467 discloses a process for stabilizing a human monoclonal antibody composition produced by hybridoma cell line having accession number HB8307, which comprises dialyzing the human monoclonal antibody in a phosphate salt stabilized buffer solution having a pH from 7.2 to 7.4, said solution comprising 1-20 mg of D-mannitol per mg of said monoclonal antibody, 0.005-0.2 millimole of glycine per mg of said monoclonal antibody, and an amount of pH stabilizing phosphate salt to stabilize the pH of said solution. [0012]
  • There is a need for a stable liquid antibody preparation, wherein the antibody concentration is 50 mg/ml or greater; such preparation is suitable for parenteral administration, including intravenous, intramuscular, intraperitoneal, or subcutaneous injection to a human. [0013]
  • SUMMARY OF THE INVENTION
  • This invention is directed to a stable liquid pharmaceutical formulation comprising a high concentration, e.g., greater than 50 mg/ml, of an antibody in 20-60 mM succinate buffer or 30-70 mM histidine buffer (pH from about pH 5.5 to about pH 6.5), a tonicity modifier, and about 0.01-0.1% polysorbate. This formulation retains the physical, chemical, and biological stability of antibody and prevents the immunoglobulins intended for administration to human subjects from forming aggregates and particulates in the final product. Preferred antibodies of this invention include Daclizumab, a humanized anti-1L-2 receptor monoclonal antibody; HAIL-12, a humanized anti-IL-12 monoclonal antibody; and HuEP5C7, a humanized anti-L selectin monoclonal antibody; and Flintozumab, a humanized anti-gamma interferon monoclonal antibody. [0014]
  • The liquid antibody formulation is stable at refrigerated temperature (2-8° C.) for at least 1 year and preferably 2 years. This liquid formulation is also stable at room temperature (23-27° C.) for at least six months. This liquid formulation is suitable for subcutaneous injection.[0015]
  • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1A shows the percent clips formation, and FIG. 1B shows the percent aggregates, at various pH levels following a four-week incubation of the sample at 45° C., as assessed by SEC-HPLC. [0016]
  • FIG. 2 shows the percent of degradation obtained at various pH levels as assessed by cIEF following a four-week incubation of the sample at 45° C. [0017]
  • FIG. 3 shows the percent of iso-aspartic acid formed at various pH levels as assessed by the Promega IsoQuant kit following a four-week incubation of the sample at 45° C. [0018]
  • FIG. 4 shows the effect of different buffers over time on potency following incubation at 37° C.[0019]
  • DETAILED DESCRIPTION OF THE INVENTION
  • I. Definition [0020]
  • As used herein, the term “buffer” encompasses those agents which maintain the solution pH in an acceptable range and may include succinate (sodium), histidine, phosphate (sodium or potassium), Tris (tris (hydroxymethyl) aminomethane), diethanolamine, and the like. The buffer of this invention has a pH in the range from about 5.5 to about 6.5; and preferably has a pH of about 6.0. Examples of buffers that will control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate phospate and other organic acid buffers. [0021]
  • “Pharmaceutically acceptable excipients” (vehicles, additives) are those inert substances that can reasonably be administered to a subject mammal and provide an effective dose of the active ingredient employed. These substances are added to a formulation to stabilize the physical, chemical and biological structure of the antibody. The term also refers to additives that may be needed to attain an isotonic formulation, suitable for the intended mode of administration. [0022]
  • The term “pharmaceutical formulation” refers to preparations which are in such form as to permit the biological activity of the active ingredients to be unequivocally effective, and which contain no additional components which are toxic to the subjects to which the formulation would be administered. [0023]
  • A “stable” formulation is one in which the protein therein essentially retains its physical stability, chemical stability, and biological activity upon storage. Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, [0024] A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time period.
  • A “stable” liquid antibody formulation is a liquid antibody formulation with no significant changes observed at a refrigerated temperature (2-8° C.) for at least 12 months, preferably 2 years, and more preferably 3 years; or at room temperature (23-27° C.) for at least 3 months, preferably 6 months, and more preferably 1 year. The criteria for stability are as follows. No more than 10%, preferably 5%, of antibody monomer is degraded as measured by SEC-HPLC. The solution is colorless, or clear to slightly opalescent by visual analysis. The concentration, pH and osmolality of the formulation have no more than +/−10% change. Potency is within 70-130%, preferably 80-120% of the control. No more than 10%, preferably 5% of clipping (hydrolysis) is observed. No more than 10%, preferably 5% of aggregation is formed. [0025]
  • An antibody “retains its physical stability” in a pharmaceutical formulation if it shows no significant increase of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering, size exclusion chromatography (SEC-HPLC) and dynamic light scattering. In addition the protein conformation is not altered. The changes of protein conformation can be evaluated by fluorescence spectroscopy, which determines the protein tertiary structure, and by FTIR spectroscopy, which determines the protein secondary structure. [0026]
  • An antibody “retains its chemical stability” in a pharmaceutical formulation, if it shows no significant chemical alteration. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often alter the protein chemical structure include hydrolysis or clipping (evaluated by methods such as size exclusion chromatography and SDS-PAGE), oxidation (evaluated by methods such as by peptide mapping in conjunction with mass spectroscopy or MALDI/TOF/MS), deamidation (evaluated by methods such as ion-exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartic acid measurement), and isomerization (evaluated by measuring the isoaspartic acid content, peptide mapping, etc.). [0027]
  • An antibody “retains its biological activity” in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared. The biological activity of an antibody can be determined, for example, by an antigen binding ELISA assay. [0028]
  • The term “isotonic” means that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 270-328 mOsm. Slightly hypotonic osmotic pressure is 250-269 and slightly hypertonic osmotic pressure is 328-350 mOsm. Osmotic pressure can be measured, for example, using a vapor pressure or ice-freezing type osmometer. [0029]
  • “Tonicity modifiers” are those pharmaceutically acceptable inert substances that can be added to the formulation to provide an isotonity of the formulation. Tonicity modifiers suitable for this invention include salts and amino acids. [0030]
  • II. Analytical Methods [0031]
  • The following criteria are important in developing a stable pharmaceutical antibody formulation. The antibody formulation contains pharmaceutically acceptable excipients. The antibody formulation is formulated such that the antibody retains its physical, chemical and biological activity. The formulation is preferably stable for at least 1 year at refrigerated temperature (2-8° C.) and 6 months at room temperature (23-27° C.). [0032]
  • The analytical methods for evaluating the product stability include size exclusion chromatography (SEC-HPLC), dynamic light scattering test (DLS), differential scanning calorimetery (DSC), iso-asp quantification, potency, UV at 340 nm, and UV spectroscopy. SEC ([0033] J. Pharm. Scien., 83:1645-1650, (1994); Pharm. Res., 11:485 (1994); J. Pharm. Bio. Anal., 15:1928 (1997); J. Pharm. Bio. Anal., 14:1133-1140 (1986)) measures percent monomer in the product and gives information of the amount of soluble aggregates and clips. DSC (Pharm. Res., 15:200 (1998); Pharm. Res., 9:109 (1982)) gives information of protein denaturation temperature and glass transition temperature. DLS (American Lab., November (1991)) measures mean diffusion coefficient, and gives information of the amount of soluble and insoluble aggregates. UV at 340 nm measures scattered light intensity at 340 nm and gives information about the amounts of soluble and insoluble aggregates. UV spectroscopy measures absorbance at 278 nm and gives information of protein concentration.
  • The iso-Asp content in the samples is measured using the Isoquant Isoaspartate Detection kit (Promega). The kit uses the enzyme Protein Isoaspartyl Methyltransferase (PIMT) to specifically detect the presence of isoaspartic acid residues in a target protein. PIMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to isoaspartic acid at the α-carboxyl position, generating S-adenosyl-L-homocysteine (SAH) in the process. This is a relatively small molecule, and can usually be isolated and quantitated by reverse phase HPLC using the SAH HPLC standards provided in the kit. [0034]
  • The potency or bioactivity of an antibody can be measured by its ability to bind to its antigen. The specific binding of an antibody to its antigen can be quantitated by any method known to those skilled in the art, for example, an immunoassay, such as ELISA (enzyme-linked immunosorbant assay). [0035]
  • III. Preparation of Antibody [0036]
  • The invention herein relates to a stable aqueous formulation comprising an antibody. The antibody in the formulation is prepared using techniques available in the art for generating antibodies, exemplary methods of which are described in more detail in the following sections. [0037]
  • The antibody is directed against an antigen of interest. Preferably, the antigen is a biologically important polypeptide and administration of the antibody to a mammal may prevent or treat a disorder. However, antibodies directed against nonpolypeptide antigens (such as tumor-associated glycolipid antigens; see U.S. Pat. No. 5,091,178) are also contemplated. [0038]
  • Where the antigen is a polypeptide, it may be a transmembrane molecule (e.g. receptor) or ligand such as a growth factor. Exemplary antigens include molecules such as renin; a growth hormone, including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoproteins; alpha-1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as factor VIIIC, factor IX, tissue factor, and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and -beta; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophage inflammatory protein (MIP-1-alpha); a serum albumin such as human serum albumin; Muellerian-inhibiting substance; relaxin A-chain; relaxin B-chain; prorelaxin; mouse gonadotropin-associated peptide; a microbial protein, such as beta-lactamase; DNase; IgE; a cytotoxic T-lymphocyte associated antigen (CTLA), such as CTLA-4; inhibin; activin; vascular endothelial growth factor (VEGF); receptors for hormones or growth factors; protein A or D; rheumatoid factors; a neurotrophic factor such as bone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5, or -6 (NT-3, NT4, NT-5, or NT-6), or a nerve growth factor such as NGF-P; platelet-derived growth factor (PDGF); fibroblast growth factor such as aFGF and bFGF; epidermal growth factor (EGF); transforming growth factor (TGF) such as TGF-α and TGF-β, including TGF-β[0039] 1, TGF-β2, TGF-β3, TGF-β4, or TGF-β5; insulin-like growth factor-I and -II (IGF-I and IGF-II); des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins; CD proteins such as CD3, CD4, CD8, CD19 and CD20; erythropoietin; osteoinductive factors; immunotoxins; a bone morphogenetic protein (BMP); an interferon such as interferon-α, -β, and -γ; colony stimulating factors (CSFs), e.g., M-CSF, GM-CSF, and G-CSF; interleukins (ILs), e.g., IL-1 to IL-12; receptors to interleukins IL-1 to IL-12; selectins such as L, E, and P-selectin; superoxide dismutase; T-cell receptors; surface membrane proteins; decay accelerating factor; viral antigen such as, for example, a portion of the AIDS envelope; transport proteins; homing receptors; addressins; regulatory proteins; integrins such as CD11a, CD11b, CD11c, CD18, an ICAM, VLA-4 and VCAM; a tumor associated antigen such as HER2, HER3 or HER4 receptor; and fragments of any of the above-listed polypeptides.
  • When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed cells, is removed, for example, by centrifugation or ultrafiltration. Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants. [0040]
  • The antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the preferred purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human Υ[0041] 1, Υ2, or Υ4 heavy chains (Lindmark et al., J. Immunol. Meth. 62:1-13 (1983)). Protein G is recommended for all mouse isotypes and for human Υ3 (Guss et al., EMBO J. 5:1567-1575 (1986)). The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. Where the antibody comprises a CH3 domain, the Bakerbond ABX™ resin (J. T. Baker, Phillipsburg, N.J.) is useful for purification. Other techniques for protein purification such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSET™ chromatography on an anion or cation exchange resin (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available depending on the antibody to be recovered.
  • Preferred antibodies encompassed by the present invention include Daclizumab (USAN, United States Adopted Names), a humanized anti-IL-2 receptor antibody. Daclizumab is currently being marketed as Zenapax® for the prevention of organ rejection after renal transplantation and is administered through the intravenous route. Daclizumab is also useful for treating psoriasis, for which, the subcutaneous delivery is the preferred route of administration. For a subcutaneous delivery of antibody, high concentration of antibody is preferred. Daclizumab is a recombinant humanized monoclonal antibody, subclass IgG1. The molecule is composed of two identical heavy chain and two identical light chain subunits. Disulfide bridges link the four chains. Daclizumab monomer is approximately 150,000 daltons in molecular weight. Daclizumab binds to the p55 subunit of the IL-2 receptor expressed on activated T cells. The antigen target is designated CD25. Daclizumab is produced from a GS-NSO cell line containing the heavy and light chain genes by fed-batch fermentation culture. Bioreactor harvests are processed to remove cells and debris and purified using a combination of ion-exchange and gel filtration chromatography and a series of ultrafiltration and filtration techniques to produce drug substance containing greater than 95% monomeric species. [0042]
  • Another preferred antibody is anti-interleukin 12 (IL-12) antibody. IL-12 is a cytokine synthesized by antigen presenting cells. It is composed of two subunits (p35 and p40), both must be present for functional activity. Functional IL-12 is also called IL-12p70. This cytokine preferentially acts on T helper cell type 1 (Th1) lymphocytes and natural killer cells by increasing their proliferative rate. One downstream effect is the secretion of interferon gamma (IFNg) by Th1 cells. Both of these functions (proliferative and IFNg production) can be easily assayed for and were used to detect IL-12 activity in samples. Certain antibodies to IL-12 have been shown to “neutralize” the above activities. Since Th1 cells have been implicated in playing a pivotal role in a variety of diseases, an antibody with neutralizing characteristics would have potential therapeutic value. 16G2 (Hoffman La Roche) is a murine antibody raised against IL-12p70. 16G2 has been shown to act in near stoichiometric amounts to IL-12 in a functional assay-the inhibition of proliferation of activated T cells from human peripheral blood (PBMC). This is an important characteristic because p40 dimers of IL-12 exist in serum and antibodies raised to the p40 subunit need to be used in excess amounts to neutralize the proliferative capacity of a given amount of IL-12. 16G2 was humanized at Protein Design Labs. (Fremont, Calif.) to give rise to HAIL-12 (humanized anti-IL-12, an IgG1 antibody). [0043]
  • Another preferred antibody is anti-L selectin antibody. Selectins, such as L, E, and P-selectin have been found to be associated with tissue damage during the course of ischemia and reperfusion. Neutrophils play an important role in this connection. It is assumed that selectin is required for the recruitment of neutrophils. L-selectin is important for the complete development of damage in skeletal muscle as well as in the lung (Seekamp, et al., [0044] Am. J. Pathol. 11:592-598 (1994). Mulligan, et al., J, Immunol. 151:832-840 (1994). HuEP5C7 (SMART Anti-L Selectin) is a humanized anti-L selectin monoclonal antibody, that contains mutant IgG2 Fc, cross reacts with both human E and P selectin antigens. It is currently being developed by Protein Design Labs, Inc. for various indications such as asthma, stroke, trauma, and certain autoimmune diseases.
  • Another preferred antibody is Flintozumab, an anti-gamma interferon antibody. Flintozumab is an IgG1 humanized monoclonal antibody developed by Protein Design Labs, Inc. for the treatment of immune disorders mediated by interferon-gamma (IFN-g), a proinflammatory cytokine. IFN-g induces the expression of major histocompatibility complex (MHC) class I and/or class II (HLA-DR) antigens, enhances the cytolytic activity of natural killer cells, activates macrophages, and modulates the immunoglobulin isotype profile of the humoral response. As a lymphokine, IFN-g also enhances the development of T helper cell type 1 (Th1), while suppressing the development of T helper cell type 2 (Th2) cells. Aberrations in the Th1/Th2 ratio have been implicated in a variety of autoimmune conditions. [0045]
  • IV. Preparation of the Formulation [0046]
  • After the antibody of interest is prepared as described above, a pharmaceutical formulation comprising the antibody is prepared. The formulation development approach is as follows: selecting the optimum solution pH, selecting buffer type and concentration, evaluating the effect of various excipients of the liquid stability, and optimizing the concentration of the screened excipients using an I-optimal experimental design (Statistics for Experimenters: An Introduction to Design, Data Analysis, and Model Building, Box, George E. P. et al., John Wiley and Sons, Inc., 1978). [0047]
  • The compositions of this invention minimize the formation of antibody aggregates and particulates and insure that the antibody maintains its bioactivity over time. The composition is a pharmaceutically acceptable liquid formulation containing a high concentration of an antibody in a buffer having a neutral or slightly acidic pH (pH 5.5-6.5), a surfactant, and a tonicity modifier. [0048]
  • The antibody in the composition is a high concentration of 50 mg/ml or greater, preferably 100 mg/ml or greater. A preferred composition of this invention contains Daclizumab, a humanized anti-IL2 receptor antibody; HAIL12, a humanized anti-IL-12 antibody; HaEP5C7, a humanized anti-L selectin antibody; and Flintozumab, a humanized anti-gamma interferon antibody. [0049]
  • A buffer of pH 5.5-6.5 is used in the composition. A buffer of pH 6.0-6.5 is preferred. Examples of buffers that control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate, phosphate, and other organic acid buffers. Succinate (pKa 5.63) is a preferred buffer for subcutaneous injection. Histidine (PK 5.97) is less preferred because of its susceptibility to oxidization, although such oxidation can be retarded by replacing the vial headspace with N[0050] 2 or adding an antioxidant. Citrate and phosphate buffers are much less preferred because it causes a painful reaction when injected subcutaneously. A preferred buffer contains about 20-60 mM sodium succinate. Another preferred buffer is 30-70 mM histidine buffer overlaid with N2.
  • A surfactant is also added to the antibody formulation. Exemplary surfactants include nonionic surfactants such as polysorbates (e.g. polysorbates 20, 80, such as Tween® 20, Tween® 80) or poloxamers (e.g. poloxamer 188). The amount of surfactant added is such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption. The surfactant may be present in the formulation in an amount from about 0.005% to about 0.5%, preferably from about 0.01% to about 0.1%, more preferably from about 0.01% to about 0.05%, and most preferably from about 0.02% to about 0.04%. [0051]
  • A tonicity modifier, which contributes to the isotonicity of the formulations, is added to the present composition. The tonicity modifier useful for the present invention includes salts and amino acids. Salts that are pharmaceutically acceptable and suitable for this invention include sodium chloride, sodium succinate, sodium sulfate, potassuim chloride, magnesium chloride, magnesium sulfate, and calcium chloride. Preferred salts for this invention are NaCl and MgCl[0052] 2. MgCl2 may also improve the antibody stability by protecting the protein from deamidation. A preferred concentration of NaCl is about 75-150 mM. A preferred concentration of MgCl2 is about 1-100 mM. Amino acids that are pharmaceutically acceptable and suitable for this invention include proline, alanine, L-arginine, asparagine, L-aspartic acid, glycine, serine, lysine, and histidine. A preferred amino acid for this invention is proline. A preferred concentration of proline is than 200 mM.
  • EDTA, which is commonly used to stabilize a protein formulation, may also be included in the formulation. EDTA, as a chelating agent, may inhibit the metal-catalyzed oxidation of the sulfhydryl groups, thus reducing the formation of disulfide-linked aggregates. A preferred concentration of EDTA is 0.01-0.2%. [0053]
  • Exemplary liquid compositions are formulations comprising antibody at about 100 mg/ml or greater, about 20-60 mM sodium succinate (pH 6), about 0.01-0.1% polysorbate 20 or 80, and about 75-150 mM NaCl. This formulation retains the stability of biological activity of the monoclonal antibody, and prevents the immunoglobulins intended for administration to human subjects from physical, chemical and biological degradation in the final product. [0054]
  • The liquid antibody formulation of this invention is suitable for parenteral administration such as intravenous, intramuscular, intraperitoneal, or subcutaneous injection; particularly suitable for subcutaneous injection. [0055]
  • The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope of the specific procedures described in them. [0056]
  • EXAMPLES Example 1 Optimization of pH
  • To identify the optimum formulation for pH range and to identify major degradation pathways, a pH profile study was conducted. Sample formulations contained 5.0 mg/ml anti-IL2 receptor antibody (Daclizumab) in one of three buffers: 50 mM sodium acetate buffer at pH 4.0 or 5.0, 50 mM histidine at pH 5.5, 6.0, or 6.5, or 50 mM sodium phosphate buffer at pH 7.0 or 8. 5. Independent formulations were incubated at either 5° C. or 45° C. with 100 RPM shaking for 4 weeks. The physical and chemical stability of each sample was assessed at 0 and 4 weeks by analytical methods including: pH and visual analysis, UV spectroscopy at 340 nm, size exclusion chromatography (SEC-HPLC), fluorescence spectroscopy, dynamic light scattering (DLS), differential scanning calorimetry (DSC), Promega IsoQuant Assay, capillary isoelectric focusing (cIEF), SDS-PAGE (reduced and non-reduced), and bioactivity assessments (ELISA). [0057]
  • SEC-HPLC performed on samples after four weeks of incubation at 45° C. showed that clipping is a major degradation pathway for the liquid formulation, as shown in FIG. 1A by the percent of clips recovered at various pH levels with SEC. Both the percent of clips and the percent of aggregates (FIG. 1B) determined by SEC were reduced at the midrange pH values of 5.5 to 6.5. [0058]
  • FIG. 2 shows the percent of degradation obtained at various pH levels as assessed by cIEF following a four-week incubation of the sample at 45° C. Minimal degradation was obtained at a pH value of about 5.5. [0059]
  • FIG. 3 shows the percent of iso-aspartic acid formed at various pH levels as assessed by the Promega IsoQuant kit following a four-week incubation of the sample at 45° C. Iso-aspartic acid formation (deamidation) was minimized at pH values of 6 and 6.5, and increased sharply at pH 8.0. [0060]
  • The results from this experiment indicate that pH 5.5 to 6.5 and preferable pH 6.0 to 6.5, are the optimal pH which minimize antibody degradation and aggregation. [0061]
  • Example 2 Optimization of Buffers
  • In this experiment, independent formulations contained 5.0 mg/ml Daclizumab antibody in 50 mM sodium succinate, pH 6.0; and 50 mM histidine, pH 6.0, with and without N[0062] 2 gassing. Sodium citrate buffer was not included because of reports of pain on subcutaneous injection. The bioactivity (potency) at time 0, and after 4, 8, and 12 weeks of incubation at 37° C. was measured by ELISA using microplates coated with recombinant human IL2 alpha receptor (IL-2 sRa) antigen, and goat anti-human IgG-HRP conjugate.
  • FIG. 4 shows the effect of different buffers over time on potency following incubation at 37° C. Highest stability of the antibody formulation was achieved through 8 weeks with 50 mM sodium succinate buffer at pH 6.0. Formulations in histidine alone rapidly (less than 8 weeks) lost their potency as the buffer oxidized. Potency of the formulation remained greater than 80% for at least 12 weeks in either sodium succinate buffer or histidine buffer gassed with N[0063] 2 to prevent oxidation.
  • Example 3 Screening of Excipients
  • Objectives [0064]
  • This study was conducted to screen various excipients for the formulation of Daclizumab antibody at 50 mg/mL. From the pH optimization study conducted earlier (Example 1), the formulation stability was maximized in the pH range of 6.0-6.5. Therefore in this study, excipients were screened in two buffers; 50 mM phosphate, pH 6.5 and 50 mM succinate, pH 6.0. The stability of antibody was monitored in the two buffers for 3 weeks at 5° C. and 45° C. with shaking at 100 RPM at a concentration of 50 mg/mL. The excipients examined included: surfactants (Tween 80® and Tween 20®), salts (NaCl and MgCl[0065] 2), antioxidants (EDTA and methionine), amino acids (glycine, lysine, serine and proline), and co-solvents (glycerol and ethanol). Various analytical techniques (clarity, pH, SEC-HPLC, UV-Vis, and cIEF) were used to characterize the excipient-containing formulations.
  • Sample Preparation [0066]
  • The Daclizumab antibody was in a 67 mM sodium phosphate formulation (without Tween® 80) at a concentration of 6.6 mg/mL. This material was concentrated to about 30 mg/mL in the Pellicon II (Millipore) unit, and subsequently, buffer exchanged into two selected buffers (50 mM sodium phosphate pH 6.5, and 50 mM sodium succinate pH 6.0) using the 50 mL amicon stir cell (Millipore). During the third and final buffer exchange step, the material was also concentrated to a final concentration of 125 mg/mL. Finally, the antibody was filtered through 0.8 μm membrane (Uniflo). The post filtration protein concentration was determined to be approximately 100 mg/mL for the phosphate buffer sample and 97 mg/mL for the succinate buffer sample. [0067]
  • The target concentration of the excipients at which they were screened is shown in Table 1. The formulations were prepared by either weighing the required amount of the excipients directly into the vial (e.g. all amino acids) or by preparing concentrated stock solutions of the excipients. The excipients were added to 0.5 mL of the appropriate buffer solution and the pH adjusted to the desired value with either 1N HCl or 10% NaOH. Subsequently, 0.5 mL of the concentrated antibody solution in the appropriate buffer (˜100 mg/mL) was added to attain the target concentration of 50 mg/mL. This procedure was adopted to prevent protein degradation due to direct contact with concentrated excipients. The 1 mL solution was split into two vials with 0.5 mL fill each. One vial was used for initial T=0 analysis and then stored at 2-8° C. for the 3 week time point analysis at 2-8° C. The other vial was incubated at 45° C. with shaking at 100 RPM for 3 weeks and analyzed at the end of that time period. [0068]
    TABLE 1
    List of excipients and their concentrations as used in the study.
    Target
    # Excipient Conc.
    1 Tween 80 0.05%
    2 EDTA 0.05%
    3 NaCl 150 mM
    4 Methionine 100 mM
    5 Glycine 200 mM
    6 Serine 200 mM
    7 Proline 200 mM
    8 Lysine 200 mM
    9 MgCl2 100 mM
    10 Tween 20 0.05%
    11 Glycerol 5.0% 
    12 Ethanol 5.0% 
  • Analytical Methods [0069]
  • At each of the two time points, the samples were analyzed using various analytical techniques. Solution clarity was visually examined by holding the sample vials up against a black background under fluorescent lighting. The solution was inspected for insoluble species and color changes were recorded. Size exclusion chromatography was performed using a Perkin Elmer HPLC unit with diode array detection and two Tosohaas columns connected in series. The samples were diluted approximately 5 fold with the corresponding buffer to bring the concentration to about 1 mg/mL and 100 μL of the sample was injected onto the column. The sample concentration was measured by UV spectroscopy using the Perkin Elmer Lambda Bio 40 spectrophotometer. [0070]
  • The samples from the 3-week time point were analyzed by Capillary Isoelectric Focusing on the BioRAD CE (BioFocus 3000) System. All the samples were diluted to 0.25 mg/mL with water and a 1:1 dilution (to a final concentration of 0.125 mg/mL) was made with the pharmalyte solution containing TEMED and two internal pI markers, 8.4 and 10.1. The capillary used was an eCAP with neutral coating (Beckmann, 56 cm length, 50 um ID). [0071]
  • The potency of samples formulated in the succinate buffer with the excipients, Tween-80, EDTA, NaCl and MgCl[0072] 2 was tested after 3 weeks of incubation at 5 and 45° C. It was a bio-assay involving KIT-225-K6 cells.
  • Results [0073]
  • There were 24 samples at time point T=0 as 12 different excipients were monitored in two different buffers. At the 3 week time point, there were 48 samples to be analyzed (12 different excipients×2 temperatures×2 buffers=48). Assays performed include concentration determination by UV-Vis, pH, Clarity, SEC-HPLC, and CIEF. [0074]
  • (a) Sample Clarity [0075]
  • Sample appearance is indicated in Table 2. All samples were clear in both the buffers at the initial time point T=0. At the 3 week time point, all samples in the phosphate buffer except the one containing lysine were clear at 5° C. In the same buffer, at 45° C., the samples containing amino acids (glycine, serine, proline and lysine) appeared clear but had some thread like floaties in the vials. The sample with MgCl[0076] 2 had clear crystals settled in the bottom of the vial.
  • In the succinate buffer, all samples except the amino acid containing formulations were clear after three weeks of incubation at 5° C. The samples with proline and lysine were the most turbid. At 45° C., all samples in succinate buffer were clear at the 3 week time point. [0077]
    TABLE 2
    Sample clarity determined by fluorescence light at T = 0 and T = 4 weeks at
    5 and 45° C. in the Na-succinate (pH 6.0) and Na-phosphate (pH 6.5) buffers.
    Phosphate Phosphate Phosphate Succinate Succinate Succinate
    T = 0 T = 3 wks T = 3 wks T = 0 T = 3 wks T = 3 wks
    Sample Clarity Clarity, 5° C. Clarity, 45° C. Clarity Clarity, 5° C. Clarity, 45° C.
    Tween-80 Clear Clear Clear Clear Clear Clear
    EDTA Clear Clear Clear Clear Clear Clear
    NaCl Clear Clear Clear Clear Clear Clear
    Methionine Clear Clear Clear Clear Turbid Clear
    Glycine Clear Clear Clear Clear Turbid Clear
    Serine Clear Clear Clear Clear Turbid Clear
    Proline Clear Clear Clear Clear Turbid Clear
    Lysine Clear Turbid Clear Clear Turbid Clear
    MgCl2 Clear Clear Clear Clear Clear Clear
    Tween-20 Clear Clear Clear Clear Clear Clear
    Glycerol Clear Clear Clear Clear Clear Clear
    Ethanol Clear Clear Clear Clear Clear Clear
  • (b) SEC-HPLC [0078]
  • Results of SEC-HPLC are tabulated in Table 3(A-C). Table 3A indicates the % monomer for all samples being investigated in this study. The % monomer at T=0 for all samples was >99%. At the three weeks time point, no significant change was observed in the % monomer for the 5° C. samples in both buffers. However, at 45° C., all samples indicated a slight drop in the % monomer (<5%). For samples formulated in the phosphate buffer, the % monomer varied from 94.08 (methionine) to 97.29 (proline), while for the samples formulated in the succinate buffer, the % monomer varied from 95.86 (methionine) to 97.55 (Tween-80). In both the buffers, the methionine and glycine containing formulations showed the most significant drop in % monomer. The decrease in % monomer was mostly due to clip formation. [0079]
  • Table 3B lists the % aggregate formation in all samples being investigated in this study. It is clear from these results that the increase in aggregate formation during the 3-week duration is minimal for all samples at 5° C. in both buffers. After 3 weeks of incubation at 45° C., samples in the phosphate buffer showed an increase in % aggregate ranging from 0.40% (EDTA) to 2.40% (glycine). In the succinate buffer, the aggregate formation was slightly lower; ranging from 0.7% (methionine) to 1.09% (glycine) after the 3 week incubation period. One of the hypotheses that supports these results is that if aggregate formation is due to oxidation, it may be slowed down in the succinate buffer due to the metal chelating properties of the succinate buffer. [0080]
  • Table 3C lists the % clip formation in all samples being investigated in this study. [0081]
  • At the initial time point, the % clipping ranged from ˜0.2-0.4% in all samples. For all samples incubated at 5° C., the % increase in clips was insignificant over the 3-week period. At 45° C., a significant increase in the rate of clip formation was observed. For samples formulated in the phosphate buffer, the % clipping varied from 4.74 (methionine) to 1.5% (proline, glycerol and ethanol), while in the succinate buffer, the range was 1.48%(Tween-80) to 3.44 (methionine). In general, an increase in the clip formation was observed in the amino acid containing formulations. Further, the rate of clip formation appears to be higher in the phosphate buffer. This may be attributed to the pH difference of the Na-succinate and Na-phosphate buffers (pH 6.0 and 6.5, respectively), indicating base catalyzed hydrolysis as being the primary reason for clip formation [0082]
    TABLE 3A
    % Monomer as determined by SEC at T = 0 and 3 weeks at 5° C. and
    45° C. in the Na-succinate (pH 6.0) and Na-phosphate (pH 6.5) buffers.
    Phosphate Phosphate Phosphate Succinate Succinate Succinate
    T = 0 T = 3 wks T = 3 wks T = 0 T = 3 wks T = 3 wks
    Sample % Mono % Mono, 5° C. % Mono, 45° C. % Mono % Mono, 5° C. % Mono, 45° C.
    Tween-80 99.36 99.48 96.71 99.43 99.51 97.55
    EDTA 99.37 99.42 96.43 99.42 99.53 97.51
    NaCl 99.37 99.41 96.84 99.42 99.53 97.31
    Methionine 99.42 99.42 94.08 99.47 99.53 95.86
    Glycine 99.41 99.42 95.90 99.46 99.53 96.46
    Serine 99.41 99.45 96.15 99.45 99.53 97.29
    Proline 99.40 99.43 97.29 99.45 99.52 97.06
    Lysine 99.34 99.62 95.45 99.45 99.57 96.28
    MgCl2 99.37 99.44 97.12 99.47 99.53 96.62
    Tween-20 99.17 99.53 96.33 99.44 99.53 97.27
    Glycerol 99.41 99.59 96.32 99.43 99.48 97.46
    Ethanol 99.41 99.42 97.24 99.31 99.19 97.42
  • [0083]
    TABLE 3B
    % Aggregate as determined by SEC at T = 0 and 3 weeks at 5° C. and
    45° C. in the Na-succinate (pH 6.0) and Na-phosphate (pH 6.5) buffers.
    Phosphate Succinate
    Phosphate Phosphate T = 3 wks Succinate Succinate T = 3 wks
    T = 0 T = 3 wks % Agg, T = 0 T = 3 wks % Agg,
    Sample % Agg % Agg, 5° C. 45° C. % Agg % Agg, 5° C. 45° C.
    Tween-80 0.41 0.00 1.61 0.36 0.36 0.96
    EDTA 0.39 0.43 0.40 0.35 0.35 0.96
    NaCl 0.40 0.43 1.23 0.33 0.34 0.85
    Methionine 0.36 0.41 1.18 0.32 0.34 0.70
    Glycine 0.38 0.42 2.40 0.33 0.35 1.09
    Serine 0.38 0.40 2.15 0.32 0.33 0.91
    Proline 0.38 0.41 1.14 0.35 0.34 0.86
    Lysine 0.39 0.36 1.50 0.32 0.30 0.64
    MgCl2 0.38 0.42 0.60 0.32 0.34 0.82
    Tween-20 0.40 0.44 1.55 0.34 0.34 1.00
    Glycerol 0.37 0.40 2.13 0.35 0.32 0.94
    Ethanol 0.37 0.43 1.26 0.28 0.38 0.91
  • [0084]
    TABLE 3C
    % Clipping as determined by SEC at T = 0 and 3 weeks at 5° C. and
    45° C. in the Na-succinate (pH 6.0) and Na-phosphate (pH 6.5) buffers.
    Phosphate Succinate
    Phosphate Phosphate T = 3 wks Succinate Succinate T = 3 wks
    T = 0 T = 3 wks % Clip, T = 0 T = 3 wks % Clip,
    Sample % Clip % Clip, 5° C. 45° C. % Clip % Clip, 5° C. 45° C.
    Tween-80 0.21 0.52 1.67 0.22 0.11 1.48
    EDTA 0.22 0.15 2.00 0.22 0.12 1.53
    NaCl 0.24 0.16 1.93 0.21 0.12 1.85
    Methionine 0.21 0.16 4.74 0.21 0.13 3.44
    Glycine 0.20 0.15 1.70 0.21 0.12 2.41
    Serine 0.21 0.14 1.69 0.23 0.12 1.81
    Proline 0.22 0.16 1.58 0.21 0.13 2.08
    Lysine 0.24 0.02 3.05 0.23 0.12 3.09
    MgCl2 0.21 0.14 2.28 0.21 0.13 2.55
    Tween-20 0.44 0.03 2.12 0.22 0.11 1.73
    Glycerol 0.23 0.01 1.54 0.22 0.20 1.61
    Ethanol 0.22 0.14 1.51 0.41 0.40 1.67
  • (c) Capillary Electrophoresis [0085]
  • All the samples from this study were analyzed by capillary electrophoresis (cIEF) on the BioRAD system. A typical cIEF profile of Daclizumab shows four peaks. Typically on accelerated aging at high temperatures, the area of the main isoform peak decreases followed by an increase in the other isoform peaks, which indicates the conversion of one isoform to another isoform. The % degradation is calculated by percent decrease in the peak area of the main isoform: [0086] % Degradation = [ Peak Area at T = 0 - Peak Area at 45 C . ] × 100 % [ Peak Area at T = 0 ]
    Figure US20030138417A1-20030724-M00001
  • Our results indicate that the 45° C. samples are more degraded in the phosphate buffer (pH 6.5) when compared with similar samples in the succinate buffer (pH 6.0). The best electropherograms were seen for the excipients, EDTA, NaCl, lysine and MgCl[0087] 2. The % degradation after 3 weeks for the 5° C. versus the 45° C. could not be calculated for the samples containing Tween 80, Tween 20, serine and proline as their electropherograms were very collapsed and the peaks indistinguishable.
  • (d) Potency [0088]
  • Based on the results of this study, the Na-succinate buffer appears to be more promising than the Na-phosphate buffer. Thus, potency assessments were done for the most stabilizing excipients in the Na-succinate buffer only. This included the formulations containing Tween-80, EDTA, NaCl and MgCl[0089] 2, subject to three weeks of incubation at 5 and 45° C. Results (Table 4) showed that the potency of all formulations was within specifications, indicating that the underlying chemical and physical degradation processes are not significantly altering the protein activity.
    TABLE 4
    Potency results of selected formulations in succinate
    buffer at T = 3 weeks at 5 and 45° C.
    Sample pH % Potency
    Tween-80, 5° C. 6.0 105
    Tween-80, 45° C. 6.0 80
    EDTA, 5° C. 6.0 103
    EDTA, 45° C. 6.0 74
    NaCl, 5° C. 6.0 105
    NaCl, 45° C. 6.0 98
    MgCl2, 5° C. 6.0 112
    MgCl2, 45° C. 6.0 96
  • Discussion [0090]
  • Based on the results of this study, the stability of formulation was higher in the Na-succinate buffer at pH 6.0, compared with the Na-phosphate buffer at pH 6.5. This is primarily due to base-catalyzed hydrolysis that is accelerated at the higher pH of 6.5, causing an increase in the rate of clip formation. Thus, the Na-succinate buffer at pH 6.0 is the selected buffer for all future studies. Results of this study also clearly indicated that in both buffers, the amino acids (glycine, lysine, serine, proline, and methionine) did not have a stabilizing effect on the protein stability. As shown by the data on sample clarity, all amino acid containing formulations indicated the formation of insoluble aggregates at 45° C. [0091]
  • The excipient MgCl[0092] 2 was selected in this study based on the hypothesis that it might protect the protein against dimidiation. While MgCl2 precipitated in the Na-phosphate buffer; in the Na-succinate buffer, based on the cIEF data, MgCl2 has a stabilizing effect on the protein. Ethanol was also included as an excipient to test if it stabilized the protein against deamidation by lowering the dielectric constant of the solution. The results, however, do not support this hypothesis. Finally, Tween-80, EDTA, and NaCl, the excipients most commonly used to stabilize protein formulations, did not show any destabilizing effect on the protein in either buffer.
  • Further experiments were conducted in the Na-succinate buffer at pH 6.0; the effect of the excipients (MgCl[0093] 2, Tween-80, NaCl, and EDTA) was further examined on the protein stability. The results indicate that to formulate an antibody at 100 mg/mL with 100 mM NaCl, the optimal concentration of Tween 80 falls in the range of 0.02-0.03%. Results also indicate that increasing the salt concentration (100-150 mM) could further stabilize the formulation. Thus, the concentration of NaCl should be maximized while maintaining the tonicity requirements. The results also indicate that the stability of the Tween 80 and NaCl containing formulation could be enhanced by adding EDTA in the concentration range of 0.35-0.5%. The addition of MgCl2 in the concentration range of 0-50 mM also could have a favorable effect. The results also indicate that the excipient concentrations for the most stable formulation are: 150 mM NaCl, 0.05% Tween 80, 0.03-0.04% EDTA and 60-70 mM MgCl2, however, these conditions are not practical because they do not provide isotonic conditions.
  • Example 4 Stability Data of Two Daclizumab Antibody Formulations in Succinate Buffer
  • Formulations 1 and 2 were prepared according to Example 3. [0094]
  • Formulation 1: 100 mg/ml Daclizumab antibody, 30 mM sodium succinate (pH 6.0) 100 mM NaC[0095] 1 and 0.03% Tween −80.
  • Formulation 2: same as Formulation 1, plus 0.05% EDTA. [0096]
  • The stability results of Formulations 1 and 2 at T=0, 2 weeks, 4 weeks, 8 weeks, and 12 weeks are shown as follows at 5, 25, and 37° C. (Table 5). [0097]
    TABLE 5
    Stability results of Formulations 1 and 2.
    %
    Sample Clarity Monomer % Clip % Aggregate % Potency
    T = 0
    F1 Clear 98.27 0.77 0.96 100
    F2 Clear 98.27 0.77 0.96 90
    T = 2 Weeks
    F1-5C Clear 98.31 0.73 0.95 NA
    F1-25C Clear 98.03 0.82 1.14 NA
    F1-37C Clear 97.11 1.21 1.69 NA
    F2-5C Clear 98.20 0.92 0.90 NA
    F2-25C Clear 97.90 1.09 1.06 NA
    T = 4 Weeks
    F1-5C Clear 98.30 0.74 0.96 93
    F1-25C Clear 97.80 0.92 1.28 88
    F1-37C Clear 96.20 1.77 2.03 84
    F2-5C Clear 98.30 0.77 0.93 94
    F2-25C Clear 97.85 0.95 1.20 92
    F2-37C Clear 96.30 1.83 1.87 80
    T = 8 Weeks
    F1-5C Clear 98.24 0.73 0.95 96
    F1-25C Clear 97.51 0.82 1.14 96
    F1-37C Clear 94.76 1.21 1.69 90
    F2-5C Clear 98.34 0.78 0.88 90
    F2-25C Clear 97.42 1.20 1.38 90
    F2-37C Clear 94.63 3.06 2.31 85
    T = 12 Weeks
    F1-5C Clear 98.25 0.73 1.02 98
    F1-25C Clear 97.07 1.26 1.62 90
    F1-37C Clear 93.31 3.88 2.81 84
    F2-5C Clear 98.30 0.70 1.00 94
    F2-25C Clear 97.22 1.30 1.48 88
    F2-37C Clear 92.88 4.05 1.54 82
  • Example 5 Stability Data of Two Daclizumab Formulations in Histidine Buffer
  • Formulations 3 and 4 are prepared according to Example 3. [0098]
  • Formulation 3: 100 mg/ml Daclizumab antibody, 50 mM histidine (pH 6.0), 115 mM NaCl, 0.03% Tween®-80, purged with nitrogen. [0099]
  • Formulation 4: same as Formulation 3, plus 0.05% EDTA. [0100]
  • The stability results of Formulations 3 and 4 at T=0, 2 weeks, 4 weeks, 8 weeks, and 12 weeks are shown as follows at 5, 25, and 37° C. (Table 6). [0101]
    TABLE 6
    Stability results of Formulations 3 and 4.
    %
    Sample Clarity Monomer % Clip % Aggregate % Potency
    T = 0
    F3 Clear 99.24 0.43 0.33 79
    F4 Clear 99.01 0.68 0.32 89
    T = 2 Weeks
    F3-5C Clear 99.24 0.38 0.38 ND
    F3-25C Clear 99.09 0.47 0.44 ND
    F3-37C Clear 98.32 1.01 0.67 ND
    F4-5C Clear 99.19 0.44 0.37 ND
    F4-25C Clear 99.11 0.47 0.42 ND
    F4-37C Clear 98.41 0.93 0.66 ND
    T = 4 Weeks
    F3-5C Clear 99.26 0.37 0.35 91
    F3-25C Clear 98.99 0.56 0.45 76
    F3-37C Clear 97.96 1.42 0.62 83
    F4-5C Clear 99.28 0.38 0.34 81
    F4-25C Clear 99.00 0.56 0.44 85
    F4-37C Clear 97.94 1.44 0.63 79
    T = 8 Weeks pH 6.0
    F3-5C Clear 99.24 0.38 0.38 86
    F3-25C Clear 98.74 0.72 0.54 82
    F3-37C Clear 96.87 2.37 0.76 75
    F4-5C Clear 99.23 0.39 0.38 97
    F4-25C Clear 98.71 0.75 0.54 92
    F4-37C Clear 96.90 2.34 0.76 86
    T = 12 Weeks pH 6.0
    F3-5C Clear 98.89 0.63 0.49 99
    F3-25C Clear 98.04 1.21 0.75 96
    F3-37C Clear 94.79 4.06 1.17 90
    F4-5C Clear 98.92 0.60 0.48 91
    F4-25C Clear 98.06 1.23 0.72 87
    F4-37C Clear 95.02 3.83 1.15 78
  • Example 6 Stability Data of Daclizumab Formulation at Room Temperature for One Year
  • A liquid antibody formulation of 100 mg/ml Daclizumab in 30 mM sodium succinate, pH 6, 100 mM NaCl, and 0.03% Tween® 80 was tested for stability after one year storage at 25° C. The stability results indicate that the formulation is stable for at least one year at 25° C. (Table 7). [0102]
    TABLE 7
    Stability Results of Daclizumab formulation
    after One-Year Storage at 25° C.
    % %
    Sample Clarity % Monomer Clip Aggregate % Potency
    T = 0 Clear 98.27 0.77 0.96 100
    T = 1 year Clear 94.32 3.14 2.53 86
  • Example 7 Stability Data of Daclizumab Formulation at 5° C. for 18 Months
  • A liquid antibody formulation of 100 mg/ml Daclizumab in 30 mM sodium succinate, pH 6, 100 mM NaCl, and 0.03% Tween® 80 was incubated at 5° C. (2-8° C.) and tested for stability at different time points. The stability results indicate that the formulation is stable for at least 18 months at refrigerated temperature (Table 8). [0103]
    TABLE 8
    Stability Results of Daclizumab at 5° C.
    Time (Month) % Monomer % Aggregate
    0 99.0 N/A
    3 99.1 0.2%
    6 99.1 0.2%
    9 98.8 0.2%
    12 98.9 0.2%
    18 98.6 0.2%
  • Example 8 Stability data of HAIL-12 (Histidine Buffer)
  • HAIL-12 (anti-IL12 antibody, 50 mg/mL) was formulated in 50 mM Histidine buffer, 120 mM sodium chloride, 0.03% Tween 80, pH 6.0. The on-going stability testing indicates that the formulation is stable at 5° C. for at least 9 months (Table 9). [0104]
    TABLE 9
    Stability Results of HAIL-12 at 5° C.
    % %
    Sample Clarity Monomer Clip % Aggregate % Potency
    T = 0 Clear 99.47 0.18 0.35 95
    T = 7 months Clear 98.90 0.65 0.45
    T = 8 months 100
    T = 9 months 98.52
  • Example 9 Stability data of HAIL-12 (Succinate Buffer)
  • HAIL-12 (50 and 100 mg/mL) was formulated in 40 mM Na-succinate buffer, 100 mM NaCl, and 0.03% Tween-80, pH 6.0. The ongoing stability testing indicates that the formulation is stable at 5, 25, and 37° C. for at least 12 weeks (Tables 10 and 11). [0105]
    TABLE 10
    Stability Results of HAIL-12 (50 mg/mL)at various temperatures.
    %
    Sample Clarity Monomer % Clip % Aggregate % Potency
    T = 0
    5° C. Clear 99.27 0.27 0.47 99
    T = 12 Weeks
    5° C. Clear 99.00 0.34 0.67 109
    25° C.  Clear 98.05 0.92 1.04 76
    37° C.  Clear 93.86 4.25 1.90 75
    T = 6 Months
    5° C. Clear 98.63 0.61 0.76 97
    25° C.  Clear 97.1 1.67 1.22 78
  • [0106]
    TABLE 11
    Stability Results of HAIL-12 (100 mg/ml) at various temperatures.
    %
    Sample Clarity Monomer % Clip % Aggregate
    T = 0
    5° C. Clear 99.2 0.31 0.49
    T = 12 Weeks
    5° C. Clear 98.9 0.31 0.78
    25° C.  Clear 97.67 0.95 1.38
    37° C.  Clear 93.26 4.14 2.6
  • Example 11 Stability data of HuEP5C7
  • HuEP5C7 (anti-L selectin antibody, 50 and 100 mg/mL) was formulated in 50 mM histidine buffer, 125 mM sodium chloride, 0.01% Tween 80, pH 6.0. The on-going stability testing indicates that the formulation is stable for three months at 25° C. and 45° C. and for at least 9 months at 5° C. The results of the 9-month stability testing at 5° C. is shown in Table 12. The results of the 3-month accelerated stability testing is shown in Table 13. [0107]
    TABLE 12
    Stability Results of HuEP5C7 at 5° C.
    %
    Sample Monomer % Clip % Aggregate % Potency
     50 mg/mL
    T = 0 98.54 0.30 1.17 83
    T = 9 months 99.08 0 0.91 99
    100 mg/mL
    T = 0 98.56 0.23 1.21 79
    T = 9 months 98.05 0.03 1.47 90
  • [0108]
    TABLE 13
    Stability Results of HuEP5C7 at various temperatures.
    %
    Sample Monomer % Clip % Aggregate % Potency
    T = 3 months
    50 mg/mL - 5° C.  99.48 0.14 0.39 121
    50 mg/mL - 25° C. 98.81 0.31 0.88 72
    50 mg/mL - 45° C. 98.26 0.99 0.76 107
    100 mg/mL - 5° C.  99.03 0 0.97 93
    100 mg/mL - 25° C.  98.56 0.40 1.06 78
    100 mg/mL - 45° C.  97.88 0.92 1.20 91
  • The invention, and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. [0109]

Claims (13)

What is claimed is:
1. A stable liquid pharmaceutical formulation comprising:
about 20-60 mM succinate buffer having pH from about pH 5.5 to about pH 6.5,
about 0.01%-0.1% polysorbate,
a tonicity modifier that contributes to isotonicity of the formulation, and
greater than 50 mg/ml antibody.
2. A stable liquid pharmaceutical formulation comprising:
about 30-70 mM histidine buffer having pH from about pH 5.5 to about pH 6.5,
about 0.01%-0.1% polysorbate,
a tonicity modifier that contributes to isotonicity of the formulation, and
greater than 50 mg/ml antibody.
3. The liquid pharmaceutical formulation according to claim 1 or 2, wherein said antibody concentration is greater than 100 mg/ml.
4. The stable liquid pharmaceutical formulation according to claim 1 or 2, wherein said tonicity modifier is NaCl or MgCl2.
5. The stable liquid pharmaceutical formulation according to claim 4, wherein said NaCl is at 75-150 mM.
6. The stable liquid pharmaceutical formulation according to claim 4, wherein said MgCl2 is at 1-100 mM.
7. The stable liquid pharmaceutical formulation according to claim 1 or 2, wherein said pH is about pH 6.0 to 6.5.
8. The stable liquid pharmaceutical formulation according to claim 1 or 2, wherein said polysorbate is at a concentration of about 0.02-0.04%.
9. The stable liquid pharmaceutical formulation according to claim 1 or 2, further comprising 0.01 to 0.5% EDTA.
10. The stable liquid pharmaceutical formulation according to claim 1 or 2, wherein said formulation is stable at about 2-8° C. for at least one year.
11. The stable liquid pharmaceutical formulation according to claim 1 or 2, wherein said formulation is stable at about 23-27° C. for at least 6 months.
12. A liquid pharmaceutical formulation comprising:
about 20-60 mM succinate buffer having pH of from about pH 5.5 to about pH 6.5,
about 0.01%-0.05% polysorbate,
about 75-150 mM sodium chloride, and
greater than 50 mg/ml antibody selected from the group consisting of Daclizumab, Flintozumab, HAIL-12, and HuEP5C7.
13. A liquid pharmaceutical formulation comprising:
about 30-70 mM histidine buffer having pH of from about pH 5.5 to about pH 6.5,
about 0.01%-0.05% polysorbate,
about 75-150 mM sodium chloride, and
greater than 50 mg/ml antibody selected from the group consisting of Daclizumab, Flintozumab, HAIL-12, and HuEP5C7.
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Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030236196A1 (en) * 2002-06-20 2003-12-25 Amgen Inc. Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing
US20040166111A1 (en) * 2002-10-24 2004-08-26 Zehra Kaymakcalan Low dose methods for treating disorders in which TNFalpha activity is detrimental
US20040191243A1 (en) * 2002-12-13 2004-09-30 Bei Chen System and method for stabilizing antibodies with histidine
US20040197324A1 (en) * 2003-04-04 2004-10-07 Genentech, Inc. High concentration antibody and protein formulations
US20040208869A1 (en) * 2003-01-30 2004-10-21 Medimmune, Inc. Uses of anti-integrin alphanubeta3 antibody formulations
US20050158303A1 (en) * 2003-04-04 2005-07-21 Genentech, Inc. Methods of treating IgE-mediated disorders comprising the administration of high concentration anti-IgE antibody formulations
US20050175603A1 (en) * 2000-10-12 2005-08-11 Genentech, Inc. Reduced-viscosity concentrated protein formulations
US20050232917A1 (en) * 2004-01-09 2005-10-20 Nicholas Pullen Antibodies to MAdCAM
US20060008415A1 (en) * 2004-06-25 2006-01-12 Protein Design Labs, Inc. Stable liquid and lyophilized formulation of proteins
US20060153846A1 (en) * 2002-08-16 2006-07-13 Hans-Juergen Krause Formulation of human antibodies for treating tnf-alpha associated disorders
US20060159653A1 (en) * 2003-02-28 2006-07-20 Chugai Seiyaku Kabushiki Kaisha Stabilized preparation containing protein
US20060182740A1 (en) * 2002-06-21 2006-08-17 Biogen Idec, Inc. Buffered formulations for concentrating antibodies and methods of use thereof
WO2006096491A2 (en) * 2005-03-08 2006-09-14 Pharmacia & Upjohn Company Llc Anti-ctla-4 antibody compositions
US20060269543A1 (en) * 2005-05-19 2006-11-30 Amgen Inc. Compositions and methods for increasing the stability of antibodies
WO2006138181A2 (en) 2005-06-14 2006-12-28 Amgen Inc. Self-buffering protein formulations
US20070065437A1 (en) * 2005-09-12 2007-03-22 Greg Elson Anti-CD3 antibody formulations
US20070148171A1 (en) * 2002-09-27 2007-06-28 Xencor, Inc. Optimized anti-CD30 antibodies
WO2007089445A2 (en) 2006-01-27 2007-08-09 Amgen Inc. Ang2 and vegf inhibitor combinations
US20070249529A1 (en) * 2003-11-28 2007-10-25 Robert Hofmeister Compositions Comprising Polypeptides
US20080112953A1 (en) * 2006-10-06 2008-05-15 Amgen Inc. Stable formulations
US20080124326A1 (en) * 2006-10-20 2008-05-29 Amgen Inc. Stable polypeptide formulations
US20080213282A1 (en) * 2006-12-21 2008-09-04 Jaby Jacob Formulations
US20080267976A1 (en) * 2005-10-06 2008-10-30 Gregory Alan Lazar Optimized Anti-Cd30 Antibodies
US20090053238A1 (en) * 2003-01-30 2009-02-26 Medimmune, Inc. Stabilized High Concentration Anti-Integrin alphavbeta3 Antibody Formulations
US20090169544A1 (en) * 2007-12-28 2009-07-02 Biolnvent International Ab Formulation
WO2010031720A2 (en) 2008-09-19 2010-03-25 F. Hoffmann-La Roche Ag Novel antibody formulation
EP2173163A1 (en) * 2007-07-06 2010-04-14 GlaxoSmithKline LLC Antibody formulations
US20100172862A1 (en) * 2008-11-28 2010-07-08 Abbott Laboratories Stable antibody compositions and methods of stabilizing same
US20100239567A1 (en) * 2009-03-06 2010-09-23 Genentech, Inc. Antibody Formulation
US20100278822A1 (en) * 2009-05-04 2010-11-04 Abbott Biotechnology, Ltd. Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
US20100285011A1 (en) * 2007-12-27 2010-11-11 Chugai Seiyaku Kabushiki Kaish High concentration antibody-containing liquid formulation
WO2011026117A1 (en) 2009-08-31 2011-03-03 Facet Biotech Corporation Use of an immunoregulatory nk cell population for monitoring the efficacy of anti-il-2r antibodies in multiple sclerosis patients
WO2011028961A2 (en) * 2009-09-04 2011-03-10 Xoma Technology Ltd. Anti-botulism antibody coformulations
US20110059079A1 (en) * 2009-09-04 2011-03-10 Xoma Technology Ltd. Antibody Coformulations
WO2011053777A1 (en) 2009-10-30 2011-05-05 Abbott Biotherapeutics Corp. Use of immunoregulatory nk cell populations for predicting the efficacy of anti-il-2r antibodies in multiple sclerosis patients
US20110236398A1 (en) * 2008-12-10 2011-09-29 Joachim Momm Antibody Formulation
WO2011008770A3 (en) * 2009-07-14 2011-12-15 Biogen Idec Ma Inc. Methods for inhibiting yellow color and peroxide formation in a composition
US20120018338A1 (en) * 2009-03-30 2012-01-26 Hoffman-La Roche Inc. Method for avoiding glass fogging
WO2011089062A3 (en) * 2010-01-19 2012-03-15 F. Hoffmann-La Roche Ag Pharmaceutical formulation for proteins
US20120201812A1 (en) * 2009-09-03 2012-08-09 Ablynx N.V. Stable formulations of polypeptides and uses thereof
US20130216525A1 (en) * 2010-03-01 2013-08-22 Cytodyn, Inc. Concentrated protein formulations and uses thereof
US8613919B1 (en) 2012-08-31 2013-12-24 Bayer Healthcare, Llc High concentration antibody and protein formulations
US8703126B2 (en) 2000-10-12 2014-04-22 Genentech, Inc. Reduced-viscosity concentrated protein formulations
AU2012200203B2 (en) * 2005-03-08 2014-07-03 Pfizer Products Inc. Anti-CTLA-4 Antibody Compositions
US8821865B2 (en) 2010-11-11 2014-09-02 Abbvie Biotechnology Ltd. High concentration anti-TNFα antibody liquid formulations
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
US20150182626A1 (en) * 2012-09-07 2015-07-02 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9265834B2 (en) 2009-03-05 2016-02-23 Ablynx N.V. Stable formulations of polypeptides and uses thereof
AU2014240252B2 (en) * 2005-03-08 2016-10-06 Pfizer Products Inc Anti-CTLA-4 Antibody Compositions
US9566311B2 (en) 2010-09-30 2017-02-14 Ferring B.V. Pharmaceutical composition
US9592297B2 (en) 2012-08-31 2017-03-14 Bayer Healthcare Llc Antibody and protein formulations
US9605051B2 (en) 2014-06-20 2017-03-28 Reform Biologics, Llc Viscosity-reducing excipient compounds for protein formulations
US20170252436A1 (en) * 2014-05-07 2017-09-07 Takeda Gmbh Liquid formulation comprising gm-csf neutralizing compound
US9855331B2 (en) 2010-09-17 2018-01-02 Baxalta Incorporated Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral pH
US10005830B2 (en) 2009-03-05 2018-06-26 Ablynx N.V. Antigen binding dimer-complexes, methods of making/avoiding and uses thereof
WO2018154320A1 (en) * 2017-02-24 2018-08-30 Arecor Limited Stabilized antibody solutions
USRE47150E1 (en) 2010-03-01 2018-12-04 Bayer Healthcare Llc Optimized monoclonal antibodies against tissue factor pathway inhibitor (TFPI)
US10307483B2 (en) 2016-10-21 2019-06-04 Amgen Inc. Pharmaceutical formulations and methods of making the same

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US20080050367A1 (en) 1998-04-07 2008-02-28 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
US20030138417A1 (en) * 2001-11-08 2003-07-24 Kaisheva Elizabet A. Stable liquid pharmaceutical formulation of IgG antibodies
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
TWI306458B (en) 2003-05-30 2009-02-21 Elan Pharma Int Ltd Humanized antibodies that recognize beta amyloid peptide
US20050136055A1 (en) * 2003-12-22 2005-06-23 Pfizer Inc CD40 antibody formulation and methods
JO3000B1 (en) 2004-10-20 2016-09-05 Genentech Inc Antibody Formulations.
US8916165B2 (en) 2004-12-15 2014-12-23 Janssen Alzheimer Immunotherapy Humanized Aβ antibodies for use in improving cognition
GT200600031A (en) 2005-01-28 2006-08-29 Formulation anti beta
DOP2006000022A (en) * 2005-01-28 2006-08-15 Wyeth Corp stabilized liquid formulations of polypeptides
JP2008546805A (en) * 2005-06-23 2008-12-25 メディミューン,エルエルシー Antibody preparation with optimal aggregation and fragmentation profile
EP1909838A2 (en) * 2005-07-29 2008-04-16 Amgen Inc. Formulations that inhibit protein aggregation
WO2007019232A2 (en) * 2005-08-03 2007-02-15 Immunogen, Inc. Immunoconjugate formulations
KR101105871B1 (en) * 2005-09-27 2012-01-16 주식회사 엘지생명과학 hFSF Aqueous Formulation
EP1962907A2 (en) * 2005-12-21 2008-09-03 Wyeth a Corporation of the State of Delaware Protein formulations with reduced viscosity and uses thereof
WO2007087344A2 (en) * 2006-01-25 2007-08-02 Taro Pharmaceuticals North America, Inc. Anti-histamine compositions and use thereof
US7863426B2 (en) 2006-04-05 2011-01-04 Abbott Biotechnology Ltd. Antibody purification
DK2011880T3 (en) 2006-04-13 2012-11-26 Chugai Pharmaceutical Co Ltd taurine transporter
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
JP5290152B2 (en) 2006-04-21 2013-09-18 ノバルティス アーゲー Antagonist anti-cd40 antibody pharmaceutical compositions
TW200806315A (en) * 2006-04-26 2008-02-01 Wyeth Corp Novel formulations which stabilize and inhibit precipitation of immunogenic compositions
AU2014268186C1 (en) * 2006-04-26 2017-12-07 Wyeth Llc Novel formulations which stabilize and inhibit precipitation of immunogenic compositions
AU2012200284B2 (en) * 2006-10-06 2014-03-06 Amgen Inc. Stable Antibody Formulations
JP5635260B2 (en) 2007-03-15 2014-12-03 中外製薬株式会社 Method for producing a polypeptide
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
ES2498040T3 (en) 2007-07-27 2014-09-24 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases with humanized anti-beta
ES2591284T3 (en) 2007-08-07 2016-11-25 Chugai Seiyaku Kabushiki Kaisha Method for the production of heterogeneous proteins
JP5334319B2 (en) 2007-09-26 2013-11-06 中外製薬株式会社 Methods for modifying the isoelectric point of the antibody by amino acid substitutions Cdr
US20110245473A1 (en) 2007-09-26 2011-10-06 Chugai Seiyaku Kabushiki Kaisha Anti-IL-6 Receptor Antibody
PE07112009A1 (en) 2007-09-26 2009-07-15 Chugai Pharmaceutical Co Ltd constant region antibody mutant
BRPI0818039A2 (en) 2007-10-15 2014-10-14 Chugai Pharmaceutical Co Ltd A method for producing a cell capable of high yield production heteroproteínas.
JO3076B1 (en) 2007-10-17 2017-03-15 Janssen Alzheimer Immunotherap Immunotherapy regimes dependent on apoe status
MX2010004397A (en) 2007-10-24 2010-06-01 Chugai Pharmaceutical Co Ltd Cell for use in the production of exogenous protein, and production process using the cell.
EP2328607A1 (en) 2008-07-16 2011-06-08 Arecor Limited Stable formulation of a therapeutic protein
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
EP2423309B1 (en) 2009-04-22 2018-01-03 Chugai Seiyaku Kabushiki Kaisha A method for producing a cell capable of high-yield production of heteroproteins
WO2010089522A1 (en) * 2009-07-16 2010-08-12 Arecor Limited Stable formulation of a therapeutic protein
CA2783715A1 (en) * 2009-12-29 2011-07-07 F. Hoffmann-La Roche Ag Novel antibody formulation
TWI505838B (en) 2010-01-20 2015-11-01 Chugai Pharmaceutical Co Ltd
EP3170508A1 (en) 2010-06-04 2017-05-24 Wyeth LLC Vaccine formulations
FR2961107B1 (en) * 2010-06-15 2012-07-27 Lab Francais Du Fractionnement human immunoglobulin composition stabilized
KR101931591B1 (en) 2010-11-04 2018-12-24 베링거 인겔하임 인터내셔날 게엠베하 Anti-il-23 antibodies
EP2471554A1 (en) * 2010-12-28 2012-07-04 Hexal AG Pharmaceutical formulation comprising a biopharmaceutical drug
ES2685079T3 (en) 2011-03-25 2018-10-05 F. Hoffmann-La Roche Ag Purification procedures novel proteins
UY34105A (en) 2011-06-03 2012-07-31 Lg Life Sciences Ltd Etanercept stable liquid formulation
CA2835242A1 (en) * 2011-06-30 2013-01-03 Genentech, Inc. Anti-c-met antibody formulations
NZ623606A (en) 2011-10-25 2015-12-24 Prothena Therapeutics Ltd Antibody formulations and methods
BR112014027372A2 (en) * 2012-05-03 2017-08-08 Boehringer Ingelheim Int anti-IL-23p19 antibodies
JP6271536B2 (en) * 2012-07-09 2018-01-31 コヒラス・バイオサイエンシズ・インコーポレイテッド Etanercept formulations that exhibit a significant reduction in macroscopic visible particles
FR2994390B1 (en) 2012-08-10 2014-08-15 Adocia Method for lowering the viscosity of protein solutions at high concentration
EP2727602A1 (en) 2012-10-31 2014-05-07 Takeda GmbH Method for preparation of a high concentration liquid formulation of an antibody
MX357936B (en) * 2012-12-13 2018-07-31 Merck Sharp & Dohme SOLUTION FORMULATIONS OF ENGINEERED ANTI-IL-23p19 ANTIBODIES.
AU2014233503A1 (en) 2013-03-15 2015-09-24 Abbvie Biotechnology Ltd. Anti-CD25 antibodies and their uses
KR20150132332A (en) * 2013-03-15 2015-11-25 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 Low concentration antibody formulations
US20150010539A1 (en) 2013-03-15 2015-01-08 Abbvie Biotherapeutics Inc. Anti-cd25 antibodies and their uses
CN103217525B (en) * 2013-03-21 2015-04-29 上海执诚生物科技股份有限公司 Composition for improving cystatin C latex coated antibody stability, stabilizer containing the same, preparation method and application thereof
KR20140119396A (en) 2013-03-29 2014-10-10 삼성전자주식회사 Liquid formulation containing a protein drug
MX2016006488A (en) 2013-11-21 2016-08-03 Genmab As Antibody-drug conjugate lyophilised formulation.
TW201601756A (en) * 2014-05-16 2016-01-16 Glaxosmithkline Intellectual Property Man Ltd Antibody formulation
EP3157947A1 (en) 2014-06-23 2017-04-26 Novartis AG Hsa-gdf-15 fusion polypeptide and use thereof
US20160030585A1 (en) 2014-06-23 2016-02-04 Novartis Ag Novel fatty acids and their use in conjugation to biomolecules
EP3157942A1 (en) 2014-06-23 2017-04-26 Novartis AG Site specific protein modifications
WO2016036918A1 (en) 2014-09-03 2016-03-10 Boehringer Ingelheim International Gmbh Compound targeting il-23a and tnf-alpha and uses thereof
CU20170093A7 (en) 2015-01-23 2017-09-06 Novartis Ag Conjugates of synthetic fatty acids and longer half-life apelin
AR104847A1 (en) * 2015-06-17 2017-08-16 Lilly Co Eli Formulation of anti-CGRP antibody
CN108367053A (en) 2015-12-22 2018-08-03 诺华股份有限公司 Methods of treating or ameliorating metabolic disorders using growth differentiation factor 15 (gdf-15)
WO2017121867A1 (en) 2016-01-13 2017-07-20 Genmab A/S Formulation for antibody and drug conjugate thereof
WO2018027195A1 (en) * 2016-08-05 2018-02-08 Abbvie Biotherapeutics Inc. Compositions containing reduced amounts of daclizumab acidic isoforms and methods for preparing the same
WO2018080196A2 (en) 2016-10-28 2018-05-03 (주)셀트리온 Stable pharmaceutical formulation
US10093731B2 (en) 2017-02-24 2018-10-09 Kindred Biosciences, Inc. Anti-IL31 antibodies for veterinary use
WO2018156367A1 (en) * 2017-02-24 2018-08-30 Kindred Biosciences, Inc. Anti-il31 antibodies for veterinary use
WO2019123427A1 (en) 2017-12-22 2019-06-27 Novartis Ag Methods of treating metabolic disorders with fgf21 variants

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091178A (en) * 1986-02-21 1992-02-25 Oncogen Tumor therapy with biologically active anti-tumor antibodies
US5744132A (en) * 1995-02-06 1998-04-28 Genetics Institute, Inc. Formulations for IL-12
US6165467A (en) * 1991-07-20 2000-12-26 Yoshihide Hagiwara Stabilized human monoclonal antibody preparation
US6171586B1 (en) * 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US6267958B1 (en) * 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US20010014326A1 (en) * 1995-07-27 2001-08-16 Genentech, Inc. Protein formulation
US6914128B1 (en) * 1999-03-25 2005-07-05 Abbott Gmbh & Co. Kg Human antibodies that bind human IL-12 and methods for producing

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989011297A1 (en) 1988-05-27 1989-11-30 Centocor, Inc. Freeze-dried formulation for antibody products
EP0448605A4 (en) * 1988-12-15 1991-11-21 Invitron Corporation Use of basic amino acids to solubilize immunoglobulins
EP0465513A1 (en) 1989-03-27 1992-01-15 Centocor, Inc. FORMULATIONS FOR STABILIZING OF IgM ANTIBODIES
AU716785B2 (en) * 1995-07-27 2000-03-09 Genentech Inc. Stabile isotonic lyophilized protein formulation
GB9610992D0 (en) * 1996-05-24 1996-07-31 Glaxo Group Ltd Concentrated antibody preparation
EP0852951A1 (en) * 1996-11-19 1998-07-15 Boehringer Mannheim Gmbh Stable lyophilized monoclonal or polyclonal antibodies containing pharmaceuticals
ES2190087T3 (en) * 1997-06-13 2003-07-16 Genentech Inc Stabilized formulation of an antibody.
KR20060127247A (en) 1999-03-25 2006-12-11 애보트 게엠베하 운트 콤파니 카게 A method for improving the activity of an antibody
AT442862T (en) * 2000-10-12 2009-10-15 Genentech Inc Low viscosity concentrated protein formulations
GB0113179D0 (en) * 2001-05-31 2001-07-25 Novartis Ag Organic compounds
US20030138417A1 (en) * 2001-11-08 2003-07-24 Kaisheva Elizabet A. Stable liquid pharmaceutical formulation of IgG antibodies

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091178A (en) * 1986-02-21 1992-02-25 Oncogen Tumor therapy with biologically active anti-tumor antibodies
US6165467A (en) * 1991-07-20 2000-12-26 Yoshihide Hagiwara Stabilized human monoclonal antibody preparation
US5744132A (en) * 1995-02-06 1998-04-28 Genetics Institute, Inc. Formulations for IL-12
US6267958B1 (en) * 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US20010014326A1 (en) * 1995-07-27 2001-08-16 Genentech, Inc. Protein formulation
US6171586B1 (en) * 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US6914128B1 (en) * 1999-03-25 2005-07-05 Abbott Gmbh & Co. Kg Human antibodies that bind human IL-12 and methods for producing

Cited By (171)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10166293B2 (en) 2000-10-12 2019-01-01 Genentech, Inc. Reduced-viscosity concentrated protein formulations
US20070116700A1 (en) * 2000-10-12 2007-05-24 Genentech, Inc. Reduced-Viscosity Concentrated Protein Formulations
US8142776B2 (en) 2000-10-12 2012-03-27 Genentech, Inc. Reduced-viscosity concentrated protein formulations
US8703126B2 (en) 2000-10-12 2014-04-22 Genentech, Inc. Reduced-viscosity concentrated protein formulations
US7666413B2 (en) 2000-10-12 2010-02-23 Genetech, Inc. Method of reducing viscosity of high concentration protein formulations
US20050175603A1 (en) * 2000-10-12 2005-08-11 Genentech, Inc. Reduced-viscosity concentrated protein formulations
US9340612B2 (en) * 2001-03-19 2016-05-17 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20150190512A1 (en) * 2001-03-19 2015-07-09 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US7700722B2 (en) 2002-06-20 2010-04-20 Amgen Inc. Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing
US20100197751A1 (en) * 2002-06-20 2010-08-05 Amgen Inc. Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing
US20030236196A1 (en) * 2002-06-20 2003-12-25 Amgen Inc. Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing
US20060182740A1 (en) * 2002-06-21 2006-08-17 Biogen Idec, Inc. Buffered formulations for concentrating antibodies and methods of use thereof
US9738714B2 (en) 2002-08-16 2017-08-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US8795670B2 (en) 2002-08-16 2014-08-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US8802102B2 (en) 2002-08-16 2014-08-12 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8802100B2 (en) 2002-08-16 2014-08-12 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US9295725B2 (en) 2002-08-16 2016-03-29 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9732152B2 (en) 2002-08-16 2017-08-15 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US8911741B2 (en) 2002-08-16 2014-12-16 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US9220781B2 (en) 2002-08-16 2015-12-29 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US8916157B2 (en) 2002-08-16 2014-12-23 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US20060153846A1 (en) * 2002-08-16 2006-07-13 Hans-Juergen Krause Formulation of human antibodies for treating tnf-alpha associated disorders
US9750808B2 (en) 2002-08-16 2017-09-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US8916158B2 (en) 2002-08-16 2014-12-23 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8932591B2 (en) 2002-08-16 2015-01-13 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8216583B2 (en) 2002-08-16 2012-07-10 Abbott Biotechnology, Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8940305B2 (en) 2002-08-16 2015-01-27 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US9302011B2 (en) 2002-08-16 2016-04-05 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-α associated disorders
US9272041B2 (en) 2002-08-16 2016-03-01 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9114166B2 (en) 2002-08-16 2015-08-25 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9289497B2 (en) 2002-08-16 2016-03-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9327032B2 (en) 2002-08-16 2016-05-03 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US8802101B2 (en) 2002-08-16 2014-08-12 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US9272042B2 (en) 2002-08-16 2016-03-01 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US20070148171A1 (en) * 2002-09-27 2007-06-28 Xencor, Inc. Optimized anti-CD30 antibodies
US20070166309A1 (en) * 2002-09-27 2007-07-19 Xencor, Inc. Optimized anti-cd30 antibodies
US20040166111A1 (en) * 2002-10-24 2004-08-26 Zehra Kaymakcalan Low dose methods for treating disorders in which TNFalpha activity is detrimental
US8846046B2 (en) 2002-10-24 2014-09-30 Abbvie Biotechnology Ltd. Low dose methods for treating disorders in which TNFα activity is detrimental
US20040191243A1 (en) * 2002-12-13 2004-09-30 Bei Chen System and method for stabilizing antibodies with histidine
US20090053238A1 (en) * 2003-01-30 2009-02-26 Medimmune, Inc. Stabilized High Concentration Anti-Integrin alphavbeta3 Antibody Formulations
US20040208869A1 (en) * 2003-01-30 2004-10-21 Medimmune, Inc. Uses of anti-integrin alphanubeta3 antibody formulations
US8765124B2 (en) * 2003-02-28 2014-07-01 Chugai Seiyaku Kabushiki Kaisha Stabilized preparation containing protein
US20060159653A1 (en) * 2003-02-28 2006-07-20 Chugai Seiyaku Kabushiki Kaisha Stabilized preparation containing protein
US20090280129A1 (en) * 2003-04-04 2009-11-12 Genentech, Inc. High concentration antibody and protein formulations
US10034940B2 (en) 2003-04-04 2018-07-31 Genentech, Inc. High concentration antibody and protein formulations
US20040197324A1 (en) * 2003-04-04 2004-10-07 Genentech, Inc. High concentration antibody and protein formulations
US20070053900A1 (en) * 2003-04-04 2007-03-08 Genentech, Inc. High concentration antibody and protein formulations
US20050158303A1 (en) * 2003-04-04 2005-07-21 Genentech, Inc. Methods of treating IgE-mediated disorders comprising the administration of high concentration anti-IgE antibody formulations
US20070086995A1 (en) * 2003-04-04 2007-04-19 Genentech, Inc. Methods of treating IgE-mediated disorders comprising the administration of high concentration anti-IgE antibody formulations
US8961964B2 (en) 2003-04-04 2015-02-24 Genentech, Inc. High concentration antibody and protein formulations
US20070249529A1 (en) * 2003-11-28 2007-10-25 Robert Hofmeister Compositions Comprising Polypeptides
US10000574B2 (en) * 2003-11-28 2018-06-19 Amgen Research (Munich) Gmbh Compositions comprising polypeptides
US20070166308A1 (en) * 2004-01-09 2007-07-19 Nicholas Pullen Antibodies to MAdCAM
US20080124339A1 (en) * 2004-01-09 2008-05-29 Nicholas Pullen Antibodies to MAdCAM
US10259872B2 (en) 2004-01-09 2019-04-16 Pfizer, Inc. Antibodies to MAdCAM
US9328169B2 (en) 2004-01-09 2016-05-03 Pfizer Inc. Human antibodies that bind human MAdCAM
US20050232917A1 (en) * 2004-01-09 2005-10-20 Nicholas Pullen Antibodies to MAdCAM
USRE45847E1 (en) 2004-01-09 2016-01-19 Pfizer Inc. Antibodies to MAdCAM
US7932372B2 (en) 2004-01-09 2011-04-26 Amgen Fremont Inc. Antibodies to MAdCAM
WO2006004736A3 (en) * 2004-06-25 2007-06-14 Pdl Biopharma Inc Stable liquid and lyophilized formulation of proteins
US20060008415A1 (en) * 2004-06-25 2006-01-12 Protein Design Labs, Inc. Stable liquid and lyophilized formulation of proteins
WO2006096490A3 (en) * 2005-03-08 2006-12-28 Corey Mathew Allan ANTI-MAdCAM ANTIBODY COMPOSITIONS
EP2620450A3 (en) * 2005-03-08 2014-01-08 Pfizer Products Inc. Anti-CTLA-4 antibody compositions
WO2006096461A3 (en) * 2005-03-08 2006-12-21 Corey M Allan Composition comprising an antibody against macrophage colony-stimulating factor (m-csf) and a chelating agent
EP2311491A1 (en) * 2005-03-08 2011-04-20 Pharmacia & Upjohn Company LLC Composition comprising an antibody against macrophage colony-stimulating factor (M-CSF) and a chelating agent
US20110027262A1 (en) * 2005-03-08 2011-02-03 Pharmacia & Upjohn Company Llc Platform antibody compositions
WO2006096491A3 (en) * 2005-03-08 2007-03-29 Pharmacia & Upjohn Co Llc Anti-ctla-4 antibody compositions
AU2014240252B2 (en) * 2005-03-08 2016-10-06 Pfizer Products Inc Anti-CTLA-4 Antibody Compositions
WO2006096488A3 (en) * 2005-03-08 2006-11-30 Tapan Kanti Das Composition comprising human igg2 antibody and chelating agent
JP2006249085A (en) * 2005-03-08 2006-09-21 Pharmacia & Upjohn Co Llc Platform antibody composition
KR100996801B1 (en) * 2005-03-08 2010-11-25 파마시아 앤드 업존 캄파니 엘엘씨 ANTI-MAdCAM ANTIBODY COMPOSITIONS
WO2006096488A2 (en) * 2005-03-08 2006-09-14 Pharmacia & Upjohn Company Llc Composition comprising human igg2 antibody and chelating agent
WO2006096490A2 (en) * 2005-03-08 2006-09-14 Pharmacia & Upjohn Company Llc ANTI-MAdCAM ANTIBODY COMPOSITIONS
WO2006096491A2 (en) * 2005-03-08 2006-09-14 Pharmacia & Upjohn Company Llc Anti-ctla-4 antibody compositions
KR100989280B1 (en) * 2005-03-08 2010-10-20 파마시아 앤드 업존 캄파니 엘엘씨 Anti-ctla-4 antibody compositions
US20080248047A1 (en) * 2005-03-08 2008-10-09 Tapan Das Platform Antibody Compositions
AU2012200203B2 (en) * 2005-03-08 2014-07-03 Pfizer Products Inc. Anti-CTLA-4 Antibody Compositions
US20090110681A1 (en) * 2005-03-08 2009-04-30 Pfizer, Inc. Anti-M-CSF Antibody Compositions
US20090130119A1 (en) * 2005-03-08 2009-05-21 Justin Abate Anti-ctla-4 antibody compositions
US20090238820A1 (en) * 2005-03-08 2009-09-24 Allan Corey M ANTI-MAdCAM ANTIBODY COMPOSITIONS
AU2006220829B2 (en) * 2005-03-08 2011-10-13 Pfizer Products Inc. Anti-CTLA-4 antibody compositions
US9487581B2 (en) 2005-03-08 2016-11-08 Pfizer Inc. Anti-CTLA-4 antibody compositions
US8858935B2 (en) 2005-05-19 2014-10-14 Amgen Inc. Compositions and methods for increasing the stability of antibodies
US20060269543A1 (en) * 2005-05-19 2006-11-30 Amgen Inc. Compositions and methods for increasing the stability of antibodies
EP3351269A1 (en) 2005-06-14 2018-07-25 Amgen Inc. Self-buffering protein formulations
WO2006138181A2 (en) 2005-06-14 2006-12-28 Amgen Inc. Self-buffering protein formulations
US20070065437A1 (en) * 2005-09-12 2007-03-22 Greg Elson Anti-CD3 antibody formulations
US7973136B2 (en) 2005-10-06 2011-07-05 Xencor, Inc. Optimized anti-CD30 antibodies
US9574006B2 (en) 2005-10-06 2017-02-21 Xencor, Inc. Optimized anti-CD30 antibodies
US20080267976A1 (en) * 2005-10-06 2008-10-30 Gregory Alan Lazar Optimized Anti-Cd30 Antibodies
WO2007089445A2 (en) 2006-01-27 2007-08-09 Amgen Inc. Ang2 and vegf inhibitor combinations
US20080112953A1 (en) * 2006-10-06 2008-05-15 Amgen Inc. Stable formulations
US8241632B2 (en) 2006-10-20 2012-08-14 Amgen Inc. Stable polypeptide formulations
US20080124326A1 (en) * 2006-10-20 2008-05-29 Amgen Inc. Stable polypeptide formulations
US20100158908A1 (en) * 2006-10-20 2010-06-24 Amgen Inc. Stable Polypeptide Formulations
US7705132B2 (en) 2006-10-20 2010-04-27 Amgen Inc. Stable polypeptide formulations
US20080213282A1 (en) * 2006-12-21 2008-09-04 Jaby Jacob Formulations
EP2173163A4 (en) * 2007-07-06 2010-12-08 Glaxosmithkline Llc Antibody formulations
EP2173163A1 (en) * 2007-07-06 2010-04-14 GlaxoSmithKline LLC Antibody formulations
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
US9085619B2 (en) 2007-11-30 2015-07-21 Abbvie Biotechnology Ltd. Anti-TNF antibody formulations
US8568720B2 (en) 2007-12-27 2013-10-29 Chugai Seiyaku Kabushiki Kaisha High concentration antibody-containing liquid formulation
US20100285011A1 (en) * 2007-12-27 2010-11-11 Chugai Seiyaku Kabushiki Kaish High concentration antibody-containing liquid formulation
US20110014203A1 (en) * 2007-12-28 2011-01-20 Fredrik Nilsson Formulation
US20090169544A1 (en) * 2007-12-28 2009-07-02 Biolnvent International Ab Formulation
US20140093512A1 (en) * 2008-09-19 2014-04-03 Hoffmann-La Roche Inc. Pharmaceutical formulation comprising an antibody against p-selectin and a sugar selected from sucrose and trehalose
WO2010031720A2 (en) 2008-09-19 2010-03-25 F. Hoffmann-La Roche Ag Novel antibody formulation
US20100074903A1 (en) * 2008-09-19 2010-03-25 Ulla Grauschopf Novel antibody formulation
WO2010031720A3 (en) * 2008-09-19 2010-09-23 F. Hoffmann-La Roche Ag Novel antibody formulation
US20100172862A1 (en) * 2008-11-28 2010-07-08 Abbott Laboratories Stable antibody compositions and methods of stabilizing same
US8623367B2 (en) 2008-12-10 2014-01-07 Novartis Ag Antibody formulation
US20110236398A1 (en) * 2008-12-10 2011-09-29 Joachim Momm Antibody Formulation
US9265834B2 (en) 2009-03-05 2016-02-23 Ablynx N.V. Stable formulations of polypeptides and uses thereof
US10005830B2 (en) 2009-03-05 2018-06-26 Ablynx N.V. Antigen binding dimer-complexes, methods of making/avoiding and uses thereof
US8318161B2 (en) 2009-03-06 2012-11-27 Genentech, Inc. Anti-oxidized LDL antibody formulation
US20100239567A1 (en) * 2009-03-06 2010-09-23 Genentech, Inc. Antibody Formulation
US20120018338A1 (en) * 2009-03-30 2012-01-26 Hoffman-La Roche Inc. Method for avoiding glass fogging
US20100278822A1 (en) * 2009-05-04 2010-11-04 Abbott Biotechnology, Ltd. Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
WO2011008770A3 (en) * 2009-07-14 2011-12-15 Biogen Idec Ma Inc. Methods for inhibiting yellow color and peroxide formation in a composition
WO2011026117A1 (en) 2009-08-31 2011-03-03 Facet Biotech Corporation Use of an immunoregulatory nk cell population for monitoring the efficacy of anti-il-2r antibodies in multiple sclerosis patients
US9884117B2 (en) * 2009-09-03 2018-02-06 Ablynx N.V. Stable formulations of polypeptides and uses thereof
US20120201812A1 (en) * 2009-09-03 2012-08-09 Ablynx N.V. Stable formulations of polypeptides and uses thereof
US8821879B2 (en) 2009-09-04 2014-09-02 Xoma Technology Ltd. Anti-botulism antibody coformulations
WO2011028961A3 (en) * 2009-09-04 2011-06-23 Xoma Technology Ltd. Anti-botulism antibody coformulations
WO2011028961A2 (en) * 2009-09-04 2011-03-10 Xoma Technology Ltd. Anti-botulism antibody coformulations
US20110059079A1 (en) * 2009-09-04 2011-03-10 Xoma Technology Ltd. Antibody Coformulations
WO2011053777A1 (en) 2009-10-30 2011-05-05 Abbott Biotherapeutics Corp. Use of immunoregulatory nk cell populations for predicting the efficacy of anti-il-2r antibodies in multiple sclerosis patients
WO2011089062A3 (en) * 2010-01-19 2012-03-15 F. Hoffmann-La Roche Ag Pharmaceutical formulation for proteins
US20130216525A1 (en) * 2010-03-01 2013-08-22 Cytodyn, Inc. Concentrated protein formulations and uses thereof
US9956165B2 (en) * 2010-03-01 2018-05-01 Cytodyn Inc. Concentrated protein formulations and uses thereof
USRE47150E1 (en) 2010-03-01 2018-12-04 Bayer Healthcare Llc Optimized monoclonal antibodies against tissue factor pathway inhibitor (TFPI)
TWI621625B (en) * 2010-09-17 2018-04-21 Baxalta Inc Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral ph
US9855331B2 (en) 2010-09-17 2018-01-02 Baxalta Incorporated Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral pH
US9566311B2 (en) 2010-09-30 2017-02-14 Ferring B.V. Pharmaceutical composition
US8821865B2 (en) 2010-11-11 2014-09-02 Abbvie Biotechnology Ltd. High concentration anti-TNFα antibody liquid formulations
US9592297B2 (en) 2012-08-31 2017-03-14 Bayer Healthcare Llc Antibody and protein formulations
US8613919B1 (en) 2012-08-31 2013-12-24 Bayer Healthcare, Llc High concentration antibody and protein formulations
US9849181B2 (en) 2012-08-31 2017-12-26 Bayer Healthcare Llc High concentration antibody and protein formulations
US20160256547A1 (en) * 2012-09-07 2016-09-08 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9346880B2 (en) * 2012-09-07 2016-05-24 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9682145B2 (en) * 2012-09-07 2017-06-20 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9757454B2 (en) 2012-09-07 2017-09-12 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9770507B2 (en) 2012-09-07 2017-09-26 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10286072B2 (en) 2012-09-07 2019-05-14 Coherus Biosciences, Inc. Methods of manufacturing stable aqueous formulations of adalimumab
US9782480B2 (en) 2012-09-07 2017-10-10 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9737600B2 (en) 2012-09-07 2017-08-22 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9808525B2 (en) 2012-09-07 2017-11-07 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9731009B2 (en) 2012-09-07 2017-08-15 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20160256545A1 (en) * 2012-09-07 2016-09-08 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9861695B2 (en) 2012-09-07 2018-01-09 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20150190513A1 (en) * 2012-09-07 2015-07-09 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9731008B2 (en) 2012-09-07 2017-08-15 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20150191538A1 (en) * 2012-09-07 2015-07-09 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9340611B2 (en) * 2012-09-07 2016-05-17 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20150182626A1 (en) * 2012-09-07 2015-07-02 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9724414B2 (en) 2012-09-07 2017-08-08 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9724415B2 (en) 2012-09-07 2017-08-08 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10286071B2 (en) 2012-09-07 2019-05-14 Coherus Biosciences, Inc. Syringe containing stable aqueous formulations of adalimumab
US10207000B2 (en) 2012-09-07 2019-02-19 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10195275B2 (en) 2012-09-07 2019-02-05 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10155039B2 (en) 2012-09-07 2018-12-18 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10159733B2 (en) 2012-09-07 2018-12-25 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10159732B2 (en) 2012-09-07 2018-12-25 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9789185B2 (en) * 2012-09-07 2017-10-17 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9782479B2 (en) * 2012-09-07 2017-10-10 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9707293B2 (en) 2012-09-07 2017-07-18 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20170252436A1 (en) * 2014-05-07 2017-09-07 Takeda Gmbh Liquid formulation comprising gm-csf neutralizing compound
US9605051B2 (en) 2014-06-20 2017-03-28 Reform Biologics, Llc Viscosity-reducing excipient compounds for protein formulations
US10307483B2 (en) 2016-10-21 2019-06-04 Amgen Inc. Pharmaceutical formulations and methods of making the same
WO2018154320A1 (en) * 2017-02-24 2018-08-30 Arecor Limited Stabilized antibody solutions

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