WO2024023843A1 - Formulation pharmaceutique d'un anticorps thérapeutique et ses préparations - Google Patents

Formulation pharmaceutique d'un anticorps thérapeutique et ses préparations Download PDF

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WO2024023843A1
WO2024023843A1 PCT/IN2023/050715 IN2023050715W WO2024023843A1 WO 2024023843 A1 WO2024023843 A1 WO 2024023843A1 IN 2023050715 W IN2023050715 W IN 2023050715W WO 2024023843 A1 WO2024023843 A1 WO 2024023843A1
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antibody
composition
formulation
buffer
discloses
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PCT/IN2023/050715
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English (en)
Inventor
Murali JAYARAMAN
Anushri CHANDRAN
Siddharth SONI
Ravi Kumar MARIKANTY
Sucheta RAJARAMAN
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Dr. Reddy’S Laboratories Limited
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Publication of WO2024023843A1 publication Critical patent/WO2024023843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/26—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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to pharmaceutical formulations of anti-CD38 antibodies, in particular the invention discloses suitable compositions for stabilizing the antibody from lower to higher concentration.
  • Formulations for each route of administration and dosage forms may be unique and, therefore, have specific requirements. Further, route of administration of a therapeutic antibody depends on various factors such as specific treatment schedule, mode of delivery, periodical follow up with physician, dosage and concentration to be administered, etc.,. Though bioavailability of a therapeutic antibody is to its maximum when administered via intravenous route of administration but, the amount of antibody that can be administered via the intravenous route is limited due to the physico-chemical properties and stability of the antibody in solution. Similarly, for high concentration antibody formulation subcutaneous route of administration is preferable but, volume of injection that can be administered may be a limitation unless a specific class of excipients are incorporated in the formulation.
  • Therapeutic antibodies are generally approved as intravenous and/or subcutaneous administrations that preferably aids administration of specific concentration and dose of antibody drugs.
  • Existing antibodies for therapeutic use are generally approved as both low and high concentrations enabling intravenous and subcutaneous respectively.
  • Majority of the approved therapeutic antibodies have been formulated in different buffer compositions/excipients for varying concentrations of antibody considering the permeability, solubility and stability of the antibody in such concentrations. Except for a few, the state of the art in the domain of antibody formulation does not substantiate use of a single, same buffer or excipients composition to stabilize a wide concentration range of an antibody.
  • the objective of the invention is to address the above, in addition to addressing rest other challenges, such as formation of aggregates, fragments and charge variants.
  • the present invention discloses a pharmaceutical formulation of a monoclonal antibody (Mab), comprising, Mab 1 or Mab2 and succinate buffer having pH of 5.0 to 6.0, wherein the buffer stabilizes the antibody at concentrations ranging from 20 mg/ml to 200 mg/ml.
  • the formulation may additionally comprise one or more pharmaceutically acceptable excipients.
  • the disclosed formulation composition (buffer and/or excipients composition) of the invention stabilizes Mabl or Mab2 antibody from lower to higher concentrations, and maintains stability under accelerated conditions.
  • the stable formulation composition of Mabl or Mab2 antibody, obtained in the specific buffer can be used to prepare low and high concentrations of antibody without varying the formulation composition.
  • a single antibody drug substance composition can be used to prepare different drug product concentrations, without a change in the buffer or excipient components (i.e., formulation composition).
  • the disclosed Mab 1 or Mab2 antibody formulations of the invention are anti-CD38 antibodies, which binds to CD38 antigen and Mabl antibody is daratumumab and Mab2 antibody is isatuximab.
  • the invention discloses a method of controlling fragmentation in anti-CD38 antibody in a high concentration formulation comprising, preparing the antibody composition in succinate buffer at a pH of 5.0 to 6.0, wherein the method controls the rate of fragmentation of the antibody.
  • the method may additionally comprise a step of addition of excipients along with the buffer.
  • the invention discloses a method of controlling charge variants formation, in particular, basic variants formation in an anti-CD38 antibody composition, by formulating the antibody in succinate buffer, wherein the method controls the formation of basic variants.
  • the invention further discloses a method of controlling pH drift in a high concentration anti-CD38 antibody composition, the method comprises preparing the antibody composition in succinate buffer at a pH 5.0 - 6.0, wherein the prepared composition controls a drift in pH, during storage.
  • the invention discloses a method of obtaining a high concentration anti ⁇
  • CD 38 antibody formulation comprising a step of preparation of the antibody in succinate buffer composition, having pH of 5.0 to 6.0, and comprising trehalose and surfactant.
  • the antibody concentration in the said composition is 50 mg/ml to 200 mg/ml.
  • the invention also discloses a method to control fragmentation in the antibody composition.
  • antibody includes whole antibodies or any antigen binding fragment (i.e.,
  • antigen-binding portion or single chains or fusions thereof.
  • abl antibody herein refers to an antibody referenced and mentioned in IMGT as “Mab/DB ID 301” with IMGT/2D structure-DB card number ID 9128. Link to the referenced
  • the tern “Mab2 antibody” herein refers to an antibody referenced and mentioned in IMGT as “Mab/DB ID 539” with IMGT/2D structure-DB card number ID 10068. Link to the referenced
  • stable formulation refers to the formulation wherein the antibody therein retains its physical stability and/or chemical stability and/or biological activity.
  • ICH Stability Testing of New Drug Substances and Products
  • An antibody "retains its physical stability” in a pharmaceutical formulation if it shows substantially no signs or minimal aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography.
  • An antibody is said to “retain its chemical stability” in a pharmaceutical formulation when it shows no or minimal formation of product variants which may include variants as a result of chemical modification of antibody of interest such as deamination, oxidation etc.
  • Analytical methods such as ion exchange chromatography and hydrophobic ion chromatography may be used to investigate the chemical product variants.
  • the term “monomer” as used herein describes antibodies consisting of two light chains and two heavy chains.
  • the monomer content of an antibody composition is typically analyzed by size exclusion chromatography (SEC).
  • SEC size exclusion chromatography
  • HMW high molecular weight
  • aggregates may include dimers, multimers, etc., and these elute first, followed by monomer, and the clipped antibody variants or degradants which may be eluted last.
  • the clipped antibody variants are known as fragments or low molecular weight species of the antibody, which can be a result of deamidation, oxidation, isomerization and/or hydrolysis.
  • the aggregate peak or the degradant peaks may not elute as a baseline separated peaks but instead as a shoulder or abnormal broad peaks.
  • main peak refers to the peak that elutes in abundance (major peak) during a cation exchange chromatography.
  • the peak that elutes earlier than the main peak, during a cation exchange chromatography, with a charge that is acidic relative to the main peak is termed acidic variant peak.
  • the peak that elutes later than the main peak, during a cation exchange chromatography, with a charge that is relatively basic than the main peak is termed as basic variant peak.
  • the main peak content can be determined by Ion exchange chromatography (IEC). There are two modes of IEC available viz., cation and anion exchange chromatography.
  • compositions/stabilizers refer to the additives or carriers, which contribute to stability of the antibody in formulation.
  • the excipients may encompass stabilizers and tonicity modifiers.
  • stabilizers and tonicity modifiers include, but not limited to, sugars, amino acids, salts, surfactants, polymers, or it’s derivatives and/or it’s combination thereof.
  • sugar/s refers to one or more monosaccharides, disaccharides, or polysaccharides or oligosaccharides.
  • sugars include, but are not limited to, sucrose, trehalose, glucose, dextrose, raffinose and others.
  • polyol refers to multiple hydroxyl group containing organic compounds. Examples of polyols include, but are not limited to, mannitol, sorbitol, and others.
  • surfactant refers to a substance that absorbs to surfaces or interfaces to reduce surface or interfacial tension.
  • Surfactants are pharmaceutically acceptable excipients used to protect the protein formulations against various stress conditions, like agitation, shearing, exposure to high temperature etc.
  • the suitable surfactants include but are not limited to polyoxyethylensorbitan fatty acid esters such as Tween 20TM or Tween 80TM, polyoxyethylenepolyoxypropylene copolymer (e.g. Poloxamer, Pluronic), sodium dodecyl sulphate (SDS) and the like or combination thereof.
  • salt refers to a substance produced by the reaction of an acid with a base.
  • a salt consists of the positive ion (cation) of a base and the negative ion (anion) of an acid.
  • salts include, but not limited to, sodium chloride, potassium chloride, magnesium chloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulfate, ammonium chloride, calcium chloride, zinc chloride and/or sodium acetate.
  • antioxidant refers to an agent that inhibits the oxidation of other molecules and is not part of buffer component.
  • Example of antioxidant is methionine.
  • visible particles refers to insoluble particulates in a liquid composition, of size measuring greater than or equal to 100 pm (>100 pm). Formation of these insoluble particulates formation may be caused by degradation of excipients present in the formulation and/or due to protein aggregation or degradation or from any leachates from the container holding the composition.
  • formulation composition has been varied for varying concentrations of the antibody to accommodate the solubility and stability of the antibody at its low and higher concentrations.
  • Use of a single buffer and excipients composition suiting/stabilizing both low and high concentrations (viz., a wide range of concentration) of antibody are minimal in the state of the art due to the multiple challenges associated with it, including fragmentation/degradation, oxidation, aggregation, etc., that is in particular, common with high concentration formulations.
  • the present invention addresses the above.
  • the present invention discloses pharmaceutical formulations of an antibody in succinate buffer, wherein the antibody is Mabl or Mab2.
  • the disclosed Mabl or Mab2 antibody formulations of the invention are anti-CD38 antibodies, which binds to CD38 antigen.
  • the present invention discloses pharmaceutical formulations of an antibody in histidine buffer, wherein the antibody is anti-CD38 antibody.
  • the invention discloses a pharmaceutical formulation of antibody comprising, anti-CD38 antibody, buffer, one or more stabilizers/pharmaceutically acceptable excipients and surfactant.
  • the buffer is an organic buffer or an inorganic buffer, and/or its salts or combinations thereof.
  • Organic buffers include succinate buffer, histidine buffer, lactate buffer or citrate buffer and inorganic buffer includes phosphate buffer.
  • the stabilizers or pharmaceutically acceptable excipients are sugar or amino acid or salt, or combinations thereof.
  • the invention discloses a pharmaceutical formulation of antibody comprising, anti-CD38 antibody, succinate buffer having pH of 5.0 to 6.0, wherein the antibody is at a concentration ranging from 20 mg/ml to 200 mg/ml.
  • the formulation further comprises one or more following excipients: sugar, sodium chloride or surfactant.
  • the formulation does not require anti-oxidants or methionine.
  • the high concentration antibody ranges from about 50 mg/ml to 200 mg/ml.
  • the invention discloses a method of stabilizing low to high concentrations of anti-CD38 antibody, in it’s aqueous formulation composition, wherein the method comprises formulating an anti-CD38 antibody in succinate buffer composition, having a pH of 5.0 to 6.0, and wherein the antibody is at a concentration ranging from 20 mg/ml to 200 mg/ml.
  • the stable composition obtained enables administration of the antibody as intravenous or subcutaneous without a change in the buffer or excipient components.
  • the invention discloses a method of preparing a stable anti-CD38 antibody in it’s liquid/aqueous composition, wherein the method comprises addition of succinate buffer to the antibody composition during pre-formulation and/or during the formulation steps of the antibody production.
  • the method additionally comprises a step of addition of one or more pharmaceutically acceptable excipients sugar, salt, amino acid or surfactant, following addition of the buffer to the antibody composition.
  • these excipients can be added along with the buffer in pre-formulation steps.
  • the invention discloses a method of controlling pH drift in a high concentration anti-CD38 antibody composition, the method comprises preparing the antibody composition in about 5 mM to 50 mM succinate buffer, at a pH ranging from pH 5.0 - pH 6.0, wherein the method controls a drift in pH in the said antibody composition.
  • the anti-CD38 antibody concentration in the said composition is 50 mg/ml to 200 mg/ml.
  • the invention discloses a method of controlling pH drift in a high concentration anti-CD38 antibody composition, the method comprises preparing the antibody composition in about 25 mM succinate buffer, pH 5.0 - 6.0, wherein the method controls a drift in pH in the said composition.
  • the anti-CD38 antibody concentration in the said composition is 50 mg/ml to 200 mg/ml.
  • the invention discloses a method of controlling fragmentation in an anti-CD38 antibody formulation, the method comprises preparation of an anti-CD38 antibody composition in succinate buffer, at a pH ranging from pH 5.0 to pH 6.0.
  • the invention discloses a method of controlling fragmentation of anti-CD38 antibody, in it’s composition, the method comprises preparing the antibody in succinate buffer having pH of 5.0 to 6.0, wherein the method controls fragmentation of the antibody in the composition.
  • the anti-CD38 antibody concentration in the said composition is 50 mg/ml to 200 mg/ml.
  • the invention discloses a method of controlling fragmentation of anti-CD38 antibody, in it’s composition, the method comprises preparing the antibody composition in about 5 mM to 50 mM succinate buffer, having a pH of about 5.0 to about 6.0, wherein the method controls fragmentation of the antibody.
  • the anti-CD38 antibody concentration in the said composition is 50 mg/ml to 200 mg/ml.
  • the invention discloses a method of maintaining monomer content of anti-CD38 antibody in it’s composition, the method comprises addition of succinate buffer to the antibody composition during pre-formulation and/or at the formulation steps of the antibody production, followed by addition of sugar and surfactant.
  • 95% or more of anti-CD38 antibody in the antibody composition is maintained in monomeric form, when stored at 40 °C for four weeks or at 25 °C for four weeks.
  • the invention discloses a method of controlling aggregation of anti- CD38 antibody in it’s composition, the method comprises addition of succinate buffer to the antibody composition during pre-formulation and/or at the formulation steps of the antibody production, followed by addition of sugar and surfactant.
  • the method controls aggregation of the anti-CD38 antibody upon storage under accelerated or stress conditions.
  • the accelerated condition is storage of antibody composition at 25 °C and stress condition is storage of sample at 40 °C.
  • the method additionally comprises addition of sodium chloride along with the addition of other excipients.
  • the invention discloses a method of controlling visible or sub-visible particle formation in anti-CD38 antibody in it’s composition, wherein the method comprises formulating an anti-CD38 antibody in succinate buffer composition, having pH of 5.0 to 6.0, wherein the method controls formation of visible or sub-visible particles of anti-CD38 antibody.
  • the invention discloses a method of controlling formation of charge variants of anti-CD38 antibody in it’s composition, the method comprises formulating an anti- CD38 antibody in succinate buffer composition having pH of 5.0 to 6.0, wherein the method controls formation of charge variants of anti-CD38 antibody.
  • the buffer herein is added during pre-formulation stage and/or at the formulation stage of the antibody production.
  • the invention discloses a method of controlling deamidation of anti- CD38 antibody in it’s composition, the method comprises formulating an anti-CD38 antibody in succinate buffer composition having pH of 5.0 to 6.0, wherein the method controls deamidation thereby formation of acidic variants of anti-CD38 antibody.
  • the buffer herein is added during pre-formulation stage and/or at the formulation stage of the antibody production.
  • the invention discloses a method of controlling basic variants formation in an anti-CD38 antibody in it’s composition, the method comprises preparation of anti- CD38 antibody in succinate buffer, wherein the method controls formation of basic variants of anti-CD38 antibody in the formulation.
  • the buffer herein is added during pre-formulation and/or at the formulation steps of the antibody production.
  • the invention discloses a pharmaceutical formulation of anti-CD38 antibody comprising, an anti-CD38 antibody, succinate buffer, trehalose and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the formulation may additionally comprise a sodium chloride.
  • the pharmaceutical formulation may not require an anti-oxidant, such as methionine, to stabilize anti-CD38 antibody.
  • the invention discloses a high concentration anti-CD38 antibody formulation, consisting essentially of, 100 mg/ml to 200 mg/ml anti-CD38 antibody, succinate buffer, sugar and surfactant.
  • the formulation further comprises sodium chloride.
  • the invention discloses a pharmaceutical formulation of anti-CD38 antibody comprising, an anti-CD38 antibody, succinate buffer, trehalose, sodium chloride and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the invention discloses a pharmaceutical formulation of high concentration anti-CD38 antibody comprising, 120 mg/ml of an anti-CD38 antibody, succinate buffer, trehalose and surfactant.
  • the formulation further comprises sodium chloride.
  • the invention discloses a pharmaceutical formulation of anti- CD38 antibody comprising, an anti-CD38 antibody, succinate buffer, sucrose, sodium chloride and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the invention discloses a pharmaceutical formulation of anti-CD38 antibody comprising, an anti-CD38 antibody, succinate buffer, mannitol, sodium chloride and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the invention discloses a high concentration anti-CD38 antibody formulation comprising, 100 mg/ml to 200 mg/ml anti-CD38 antibody, succinate buffer, sugar and surfactant, optionally containing sodium chloride, and wherein the formulation does not contain methionine.
  • the invention discloses a high concentration anti-CD38 antibody formulation comprising, 100 mg/ml to 200 mg/ml anti-CD38 antibody, succinate buffer, sugar and surfactant, optionally containing sodium chloride.
  • the invention discloses a high concentration anti-CD38 antibody formulation comprising, 100 mg/ml to 200 mg/ml anti-CD38 antibody, succinate buffer, sugar and surfactant, optionally containing sodium chloride, and wherein the formulation does not contain methionine.
  • the invention discloses pharmaceutical formulation of anti-CD38 antibody comprising an anti-CD38 antibody, histidine buffer having pH of 5.0 to 6.0, sugar and surfactant.
  • the anti-CD38 antibody formulation further comprises sodium chloride.
  • the invention discloses pharmaceutical formulation of anti-CD38 antibody comprising, an anti-CD38 antibody, histidine buffer, trehalose and sodium chloride.
  • the disclosed formulation of anti-CD38 antibody may not require an anti-oxidant/methionine to stabilize the antibody at higher concentrations.
  • the formulation further comprises surfactant.
  • the invention discloses a method of preparing an anti-CD38 antibody composition, the method comprises addition of histidine buffer to the antibody composition during pre-formulation and/or at the formulation steps of the antibody production.
  • the method further comprises a step of addition of one or more pharmaceutically acceptable excipients sugar, salt, amino acid or surfactant, following addition of histidine buffer to the antibody composition.
  • the invention discloses a method of stabilizing an anti-CD38 antibody in it’s liquid/aqueous composition, the method comprises formulating the Mabl antibody in histidine buffer composition having pH of 5.0 to 6.0, wherein the method stabilizes the antibody at a concentration ranging from 20 mg/ml to 200 mg/ml.
  • the formulation further comprises one or more following excipients: sugar, sodium chloride or surfactant.
  • the invention discloses a method of stabilizing low to high concentrations of anti-CD38 antibody, in it’s aqueous formulation composition, the method comprises formulating the anti-CD38 antibody in histidine buffer composition having pH of 5.0 to 6.0, wherein the antibody is at a concentration ranging from 20 mg/ml to 200 mg/ml.
  • the stable composition obtained enables administration of the antibody as intravenous or subcutaneous without a change in the buffer or excipient components.
  • the invention discloses a method of maintaining monomer content of anti-CD38 antibody, in it’s composition, the method comprises addition of histidine buffer to the antibody composition during pre-formulation and/or at the formulation steps of the antibody production, followed by addition of sugar and surfactant.
  • 95% or more of anti-CD38 antibody in the antibody composition is maintained in monomeric form when stored at 40 °C for four weeks or at 25 °C for four weeks.
  • the invention discloses a method of controlling aggregation of anti- CD38 antibody, in it’s composition, the method comprises addition of histidine buffer to the antibody composition during pre-formulation and/or at the formulation steps of the antibody production, followed by addition of sugar and sodium chloride.
  • the invention discloses a method of controlling formation of charge variants of anti-CD38 antibody in it’s composition
  • the method comprises formulation of anti- CD38 antibody in histidine buffer composition having pH of 5.0 to 6.0, wherein the method controls formation of charge variants of anti-CD38 antibody in it’s composition.
  • the buffer herein is added during pre-formulation stage and/or at the formulation stage of the antibody production.
  • the invention discloses a pharmaceutical formulation of anti-CD38 antibody comprising, anti-CD38 antibody, histidine buffer, trehalose and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the formulation optionally comprises sodium chloride.
  • the invention discloses a pharmaceutical formulation of anti-CD38 antibody comprising, anti-CD38 antibody, histidine buffer, mannitol and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the invention discloses a pharmaceutical formulation of anti-CD38 antibody comprising, an anti-CD38 antibody, histidine buffer, sucrose, sodium chloride and surfactant, wherein the antibody in the pharmaceutical formulation is stable at a concentration range from about 20 mg/ml to 200 mg/ml.
  • the invention discloses an aqueous or liquid formulations of anti-CD38 antibody as disclosed in Table 1.
  • Table 1 aqueous antibody formulations of anti-CD38 antibody.
  • the surfactant can be poloxamer.
  • the concentration of the antibody in the antibody composition or formulation is about 20 mg /ml to about 200 mg/ml.
  • the concentration of the antibody in the formulation is 20 mg/ml or 30 mg/ml or 40 mg/ml or 50 mg/ml or 60 mg/ml or 80 mg/ml or 100 mg/ml or 110 mg/ml or 120 mg/ml or 130 mg/ml or 140 mg/ml or 150 mg/ml or 160 mg/ml, or 170 mg/ml or 180 mg/ml or 190 mg/ml or 195 mg/ml or 200 mg/ml.
  • the claimed compositions of anti-CD38 antibody is suitable to formulate daratumumab or isatuximab antibody.
  • the Mabl and Mab2 antibodies are anti-CD38 antibodies, which binds to CD38 antigen.
  • the Mabl antibody is daratumumab and the Mab2 antibody is isatuximab.
  • the disclosed formulations may be free of anti-oxidant.
  • the anti-oxidant is methionine.
  • viscosity of anti-CD38 antibody formulation is less than 20 cP.
  • viscosity of high concentration anti-CD38 antibody is less than 10 cP. More specifically, viscosity of anti-CD38 antibody formulation is less than 6 cP, wherein the concentration of antibody is 120 mg/ml.
  • pH of anti-CD38 antibody formulation is from 5.0 to 6.0.
  • the formulations are free of visible particles.
  • the disclosed formulations or the methods of the invention are stable at room temperature (i.e., about 25 °C) or at 40°C for one day to four weeks.
  • the formulation of anti-CD38 antibody is a stable liquid (aqueous) formulation, which can be used for parenteral administration.
  • Parenteral administration includes intravenous, subcutaneous, intra peritoneal, intramuscular administration or any other route of delivery generally considered to be falling under the scope of parenteral administration and as is well known to a skilled person.
  • the stable liquid/aqueous formulation is suitable and can be lyophilized as lyophilized powders. Further, the lyophilized formulation of anti-CD38 antibody can be reconstituted with appropriate diluent to achieve the liquid formulation suitable for administration.
  • liquid/aqueous anti-CD38 antibody are compatible with lyophilization process and the lyophilization process does not impact quality attributes of the antibody.
  • a vial, pre-filled syringe or autoinjector device or any other suitable device comprising any of the subject formulations described herein.
  • the aqueous formulation, stored in the vial or pre-filled syringe or an auto injector device comprises anti-CD38 antibody, succinate buffer or it’s derivatives or combination thereof, sugar, and surfactant.
  • the claimed formulations of anti-CD38 antibody are suitable for treatment of multiple myeloma.
  • Mabl antibody suitable for storage in the present pharmaceutical composition is produced by standard methods known in the art.
  • Mabl antibody which is an anti-CD38 antibody (daratumumab) is prepared by recombinant expression of immunoglobulin light and heavy chain genes in a mammalian host cell such as Chinese Hamster Ovary cells.
  • the expressed Mabl antibody is harvested and the crude harvest is subjected to standard downstream process steps that include purification, filtration and optionally dilution or concentration steps.
  • the crude harvest of Mabl antibody may be purified using standard chromatography techniques such as affinity chromatography, ion-exchange chromatography and combinations thereof.
  • the purified Mab 1 antibody solution can additionally be subj ected to one or more filtration steps, and the solution obtained is subjected to further formulation studies.
  • Example 1 Formulation of antibody in specific buffers and stabilizers
  • Mabl antibody approximately, 20 mg/ml in acetate buffer background was obtained from downstream chromatographic steps. Post which, Mabl antibody in acetate buffer was buffer exchanged with either histidine or succinate buffer. Excipients, sucrose or trehalose or mannitol, sodium chloride and polysorbate-20 were added to the buffer or buffer exchanged formulation based on the requirement of final composition of a formulation. The final composition of all Mabl antibody formulations are given in Table 2.
  • Table 3(a) High molecular weight content (i.e., aggregate content) of formulations as measured by SEC. W-indicates weeks, TO-represents data at zero time point
  • Table 3(c) Low molecular weight content of formulations as measured by SEC.
  • Table 4(b) Main peak content of formulations as measured by IEX, W-indicates weeks, TO-represents data at zero time point
  • Table 4(c) Basic variants content of formulations as measured by IEX
  • Example 2 High concentration Mabl antibody formulations Purified Mabl antibody approximately 20 mg/ml in acetate buffer background was obtained from downstream chromatographic steps. And, Mabl antibody in acetate buffer was buffer exchanged with succinate buffer or alternatively with a histidine buffer in a separate experiment. The buffer exchanged antibody (in it’s respective buffer composition) was concentrated upto 190 mg/ml to obtain high concentration Mabl antibody formulation. The concentration of the obtained high concentration Mabl antibody was further adjusted to 120 mg/ml and one or more excipients such as sorbitol, trehalose, methionine, polysorbate-20 were added.
  • excipients such as sorbitol, trehalose, methionine, polysorbate-20 were added.
  • Viscosity of a few formulations are measured using m-VROC® viscometer at room temperature and viscosity of these two formulations found to be in the range of 5.3 mPa.s to 5.8 mPa.s.
  • Table 6 High concentration Mabl antibody formulations prepared as per example-2.
  • Table 7 HMW, monomer, and LMW content of formulations prepared as per example-2, measured by SEC.

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Abstract

La présente invention concerne des formulations pharmaceutiques d'anticorps anti-CD38. En particulier, l'invention concerne une composition stabilisant les anticorps contre leur concentration inférieure à plus élevée. La composition stable ainsi obtenue peut être formulée sous forme de formulations intraveineuses et sous-cutanées avec les concentrations d'anticorps souhaitées, permettant une utilisation thérapeutique. La composition préparée régule en outre la fragmentation de l'anticorps pendant le stockage.
PCT/IN2023/050715 2022-07-26 2023-07-26 Formulation pharmaceutique d'un anticorps thérapeutique et ses préparations WO2024023843A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015009726A2 (fr) * 2013-07-15 2015-01-22 The Board Of Trustees Of The Leland Stanford Junior University Utilisations médicales d'agonistes de cd38
WO2017054646A1 (fr) * 2015-09-28 2017-04-06 江苏恒瑞医药股份有限公司 Préparation pharmaceutique d'anticorps anti-pd-1 stable et application de celle-ci dans un médicament
WO2020219681A1 (fr) * 2019-04-23 2020-10-29 Sanofi Formulations et anticorps anti-cd38
US20210188996A1 (en) * 2019-12-05 2021-06-24 Sanofi-Aventis U.S. Llc Formulations of anti-cd38 antibodies for subcutaneous administration
US20220218607A1 (en) * 2019-04-23 2022-07-14 Sanofi Stable, low-viscosity antibody formulations and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015009726A2 (fr) * 2013-07-15 2015-01-22 The Board Of Trustees Of The Leland Stanford Junior University Utilisations médicales d'agonistes de cd38
WO2017054646A1 (fr) * 2015-09-28 2017-04-06 江苏恒瑞医药股份有限公司 Préparation pharmaceutique d'anticorps anti-pd-1 stable et application de celle-ci dans un médicament
WO2020219681A1 (fr) * 2019-04-23 2020-10-29 Sanofi Formulations et anticorps anti-cd38
US20220218607A1 (en) * 2019-04-23 2022-07-14 Sanofi Stable, low-viscosity antibody formulations and uses thereof
US20210188996A1 (en) * 2019-12-05 2021-06-24 Sanofi-Aventis U.S. Llc Formulations of anti-cd38 antibodies for subcutaneous administration

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