Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
  • C07K16/244—Interleukins [IL]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• the DF buffer comprises about 155 mM to about 185 mM glutamate, e.g., about 150 mM arginine base and about 170 mM glutamate.
• the pH of the DF buffer is about the same as the final pH of the prepared liquid composition.
• the final pH of the prepared liquid composition is about 4.5 to about 5.5, optionally, about 4.7 to about 5.3.
• the surfactant is PS80 and/or is present at a final concentration of about 0.01% (w/v).
• a liquid composition prepared by the presently disclosed method is provided herein. [0007]
• the present disclosure additionally provides an article of manufacture comprising any one of the presently disclosed isotonic liquid compositions.
• Methods of treating a disease in a subject are provided by the present disclosure.
• the method comprises administering to the subject an isotonic liquid composition of any one of the preceding claims in an amount effective to treat the disease.
• use of the isotonic liquid composition of the present disclosure for treating a disease is provided.
• Figure 1 is a graph of the % HMW species formed in the indicated antibody formulations having the indicated target antibody concentrations.
• DETAILED DESCRIPTION [0013]
• the present disclosure provides liquid compositions comprising high concentrations of an antibody, e.g., a monoclonal antibody.
• a variable region typically comprises at least three heavy or light chain CDRs (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service N.I.H., Bethesda, Md.; see also Chothia and Lesk, 1987, J. Mol. Biol.196:901-917; Chothia et al., 1989, Nature 342: 877-883), within a framework region (designated framework regions 1-4, FR1, FR2, FR3, and FR4, by Kabat et al., 1991; see also Chothia and Lesk, 1987, supra).
• Antibodies can comprise any constant region known in the art. Human light chains are classified as kappa and lambda light chains.
• Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
• IgG has several subclasses, including, but not limited to IgG1, IgG2, IgG3, and IgG4.
• IgM has subclasses, including, but not limited to, IgM1 and IgM2.
• Embodiments of the present disclosure include all such classes or isotypes of antibodies.
• the light chain constant region can be, for example, a kappa- or lambda-type light chain constant region, e.g., a human kappa- or lambda-type light chain constant region.
• the liquid composition comprises about 100 mM to about 200 mM arginine and about 100 mM to about 200 mM glutamate.
• the liquid composition comprises about 125 mM to about 175 mM arginine or about 125 to about 150 mM arginine and about 125 mM to about 200 mM glutamate or about 140 mM to about 185 mM glutamate.
• the liquid composition comprises about 136 mM arginine base and about 159 mM glutamate.
• the composition comprises about 100 mM to about 200 mM arginine and about 100 mM to about 200 mM glutamic acid.
• an antibody formulated with about 25 mM to about 190 mM arginine and about 25 mM to about 200 mM glutamic acid in various aspects, means that the DF buffer into which the antibody was exchanged or with which the antibody was combined comprised about 25 mM to about 190 mM arginine and about 25 mM to about 200 mM glutamic acid.
• the antibody is formulated with about 50 mM to about 300 mM arginine or 85 mM to about 190 mM arginine.
• the antibody is formulated in about 55 mM to about 135 mM L- arginine base (e.g., about 55 mM to about 125 mM, about 55 mM to about 115 mM, about 55 mM to about 105 mM, about 55 mM to about 95 mM, about 55 mM to about 85 mM, about 55 mM to about 75 mM, about 55 mM to about 65 mM, about 65 mM to about 135 mM, about 75 mM to about 135 mM, about 85 mM to about 135 mM, about 95 mM to about 135 mM, about 105 mM to about 135 mM, about 115 mM to about 145 mM, about 125 mM to about 135 mM, about 75 mM to about 115 mM, about 85 mM to about 105 mM L-arginine base) and about 130 mM to
• the antibody is formulated in about 70 mM to about 210 mM arginine base and about 80 mM to about 240 mM glutamate. In various aspects, the antibody is formulated in about 100 mM to about 170 mM arginine base or about 120 mM to about 150 mM arginine base and about 120 mM to about 200 mM glutamate or about 140 mM to about 175 mM glutamate. In various aspects, the antibody is formulated in about 136 mM arginine base and about 159 mM glutamate.
• the liquid compositions of the present disclosure comprise about 170 mM to about 290 mM proline, optionally, about 200 mM to about 255 mM proline, e.g., about 230 mM proline. In exemplary aspects, the liquid compositions of the present disclosure comprise about 100 mM to about 300 mM L-proline.
• the buffer can have a pKa within one pH unit of pH 5.0-5.2 at 25 oC.
• One such buffer is acetic acid /acetate, having a pKa of about 4.75 at 25 oC.
• Other alternative buffers contemplated include buffers based on ions including succinate (pKa of 4.21 at 25 oC), propionate (pKa of 4.87 at 25 oC), malate (pKa of 5.13 at 25 oC), pyridine (pKa of 5.23 at 25 oC) and piperazine (pKa of 5.33 at 25 oC).
• the liquid composition comprises, per mL of the liquid composition, (i) about 150 mg ordesekimab, (ii) about 23 mg to about 30 mg proline, (iii) about 0.5 mg to about 2 mg acetate, and (iv) about 0.01% (w/v) polysorbate 80 (PS80), wherein the liquid composition has a pH of about 4.5 to about 5.5.
• the liquid composition comprises, per mL of the liquid composition, (i) about 150 mg ordesekimab, (ii) about 26.5 mg proline, (iii) about 1.2 mg acetate, and (iv) about 0.01 mg PS80, wherein the liquid composition has a pH of about 5.0.
• the pH is about 4.7. In various aspects, the pH is about 4.7 to about 5.3, optionally, about 5.0.
• the liquid composition is characterized by a reduced viscosity, relative to a liquid composition not comprising arginine glutamate or proline (e.g., compared to a liquid composition comprising 5%-10% (w/v) sucrose).
• the amount of main peak can be, for example in a range of about 95% to about 99.9% antibody main peak, or about 96% to about 99.9% antibody main peak, or about 97% to about 99.9% antibody main peak, or about 97.5% to about 99.9% antibody main peak, or about 98% to about 99.9% antibody main peak, or about 98.1% to about 99.9% antibody main peak, or about 98.2% to about 99.9% antibody main peak, or about 98.3% to about 99.9% antibody main peak, or about 98.4% to about 99.9% antibody main peak, or about 98.5% to about 99.9% antibody main peak, or about 98.6% to about 99.9% antibody main peak, optionally, as measured by SE-UHPLC.
• less than 5% e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) HMW species is detected by SEC, after storage at 2oC to 8oC for at least or about 12 months.
• less than 5% e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) HMW species is detected by SEC, after storage at 2oC to 8oC for about 20 months to about 26 months.
• the target concentration of the antibody is about 120 mg/mL to about 250 mg/mL, optionally, about 120 mg/mL to about 240 mg/mL, about 120 mg/mL to about 230 mg/mL, about 120 mg/mL to about 220 mg/mL, about 120 mg/mL to about 210 mg/mL, about 120 mg/mL to about 200 mg/mL, about 120 mg/mL to about 190 mg/mL, about 120 mg/mL to about 180 mg/mL, about 120 mg/mL to about 170 mg/mL, about 120 mg/mL to about 160 mg/mL, about 120 mg/mL to about 150 mg/mL, about 120 mg/mL to about 140 mg/mL, about 120 mg/mL to about 130 mg/mL, about 130 mg/mL to about 250 mg/mL, about 140 mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, about 160 mg/mL to about 250 mg/m/
• the DF buffer comprises proline at a concentration of about 200 mM to about 325 mM, about 200 mM to about 300 mM, about 200 mM to about 275 mM, about 200 mM to about 250 mM, about 200 mM to about 225 mM, about 225 mM to about 350 mM, about 250 mM to about 350 mM, about 275 mM to about 350 mM, about 300 mM to about 350 mM, or about 325 mM to about 350 mM.
• FIG.3 illustrates the pathophysiology of celiac and refractory celiac disease, as described by Schuppan et al.
• the proportion of aberrant IELs reaches or exceeds 20%, patients are diagnosed with Type II RCD (RCD-II).
• RCD-II Type II RCD
• the IELs are typically monoclonal and the risk of developing EATL is dramatically increased to greater than 50% (Nijeboer et al., 2015).
• the disease is a cancer or solid tumor.
• the cancer treatable by the methods disclosed herein can be any cancer, e.g., any malignant growth or tumor caused by abnormal and uncontrolled cell division that may spread to other parts of the body through the lymphatic system or the blood stream.
• the cancer in some aspects is one selected from the group consisting of acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, non- Hodgkin lymphoma, ovarian cancer, pan
• the liquid composition of embodiment 17 or 18, comprising a HC variable region of SEQ ID NO: 17 and a LC variable region of SEQ ID NO: 18.
• 20 The liquid composition of any one of embodiments 17 to 19, comprising a HC of SEQ ID NO: 19 and a LC of SEQ ID NO: 20.
• 21 The liquid composition of embodiment 20, wherein the monoclonal antibody binds to Glucocorticoid-Induced TNFR-Related (GITR). 22.
• the liquid composition of embodiment 26, comprising a HC CDR1 of SEQ ID NO: 31, a HC CDR2 of SEQ ID NO: 32, a HC CDR3 of SEQ ID NO: 33, a LC CDR1 of SEQ ID NO: 34, a LC CDR2 of SEQ ID NO: 35, and a LC CDR3 of SEQ ID NO: 36. 28.
• 52. The liquid composition of any one of embodiments 2-51, wherein the buffer is selected from the group consisting of: succinate, glutamate, histidine, and acetate.
• the liquid composition of embodiment 52, wherein the buffer is acetate.
• the liquid composition of embodiment 53, wherein the acetate is prepared with glacial acetic acid. 55.
• a method of preparing a liquid composition comprising a target concentration of a monoclonal antibody, wherein the target concentration is greater than about 100 mg/mL, said method comprising (a) combining the monoclonal antibody with a diafiltration (DF) buffer comprising (i) about 50 mM to about 300 mM arginine base and (ii) an amount of glutamate to achieve a molar ratio of arginine to glutamate of about 0.7:1.0 to about 1.1:1.0, and (b) adding a surfactant.
• DF diafiltration
• the liquid composition of embodiment 116 comprising about 135 mg/mL to about 165 mg/mL anti-IL-15 antibody.
• the liquid composition of embodiment 117 comprising about 140 mg/mL to about 160 mg/mL anti-IL-15 antibody.
• the liquid composition of embodiment 118 comprising about 150 mg/mL anti-IL-15 antibody.
• the liquid composition of any one of embodiments 92-116 comprising about 145 mg/mL to about 182 mg/mL anti-IL-15 antibody.
• the liquid composition of embodiment 120 comprising about 155 mg/mL to about 175 mg/mL anti-IL-15 antibody.
• the liquid composition of embodiment 121 comprising about 165 mg/mL anti-IL-15 antibody. 123.
• liquid composition of any one of embodiments 92-143 wherein the composition has an osmolality in a range of about 200 mOsm/kg to about 500 mOsm/kg, optionally, about 225 mOsm/kg to about 400 mOsm/kg, or. 146.
• the liquid composition of embodiment 145 wherein the composition has an osmolality in a range of about about 250 mOsm/kg to about 350 mOsm/kg. 147.
• Part A In the first study (Part A), eight formulations were prepared by diafiltering an initial solution comprising Antibody 1, acetate and sucrose against a diafiltration (DF) buffer. A total of 10 buffer changes were carried out to achieve a complete buffer exchange. Using an ultrafiltration/diafiltration (UF/DF) system, the buffer-exchanged Antibody 1 solution was concentrated to about 200 mg/mL Antibody 1.
• UF/DF ultrafiltration/diafiltration
• Part B In the second study (Part B), seven formulations of Antibody 1 were prepared as essentially described above. This study tested two target concentrations of Antibody 1 (150 mg/mL and 165 mg/mL) and two pHs (4.7 and 5.2). PS80 was added to a final concentration of 0.01% for all formulations except for Formulation 5b, which had a final PS80 concentration of 0.005% (w/v). Table 5 summarizes the DF buffer used to make each formulation. The osmolality for each formulation was measured and found to be within a range of about 280 mOsm/kg to about 331 mOsm/kg. TABLE 5

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