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• • 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
• • 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
  • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
• • 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
  • A61K47/06—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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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
  • A61K9/08—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/515—Complete light chain, i.e. VL + CL
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• • 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

• Prolactin is a polypeptide hormone composed of 199 amino acids.
• PRL belongs to the growth hormone (GH), placental lactogen (PL) family of polypeptide hormones and is synthesized in lactotroph cells of the pituitary and in several extrapituitary tissues such as lymphocytes, mammary epithelial cells, the myometrium, and the prostate.
• GH growth hormone
• PL placental lactogen
• PRL binds to the PRL receptor (PRLR), a single transmembrane receptor belonging to the class 1 cytokine receptor superfamily (Endocrine Reviews 19:225- 268 (1998)).
• PRLR exists in three different isoforms, the short, the long, and the intermediate form that can be distinguished by the length of their cytoplasmic tails.
• PRLR Upon ligand binding, a sequential process leads to PRLR activation.
• PRL interacts via its binding site 1 with one PRLR molecule and then attracts via its binding site 2 a second receptor molecule leading to an active dimer of PRLRs.
• PRLR dimerization leads to the predominant activation of the JAK STAT (Janus Kinase/Signal transducers and activators of transcription) pathway.
• JAKs Predominantly JAK2
• PRLR is also phosphorylated and can bind to SH2-domain containing proteins such as STATs.
• Receptor bound STATs are subsequently phosphorylated, dissociate from the receptor and translocate to the nucleus where they stimulate transcription of target genes.
• activation of the Ras-Raf-MAPK pathway and activation of the cytoplasmic src kinase by PRLRs have been described (for review Endocrine Reviews 19: 225-268 ( 1998)).
• PRLR-mediated signalling The role of PRLR-mediated signalling has been investigated in the context of the benign disease endometriosis.
• Antibodies may be administrated to patients via intravenous, intramuscular, and/or subcutaneous injection.
• intramuscular and subcutaneous injection dosage forms be isotonic and include small injection volumes ( ⁇ 2 ml per injection site).
• small injection volumes ⁇ 2 ml per injection site.
• antibodies are often administered with a wide concentration range, from 1 mg/ml to 150 mg/mL, including high concentrations within the range of 20 mg/ml to 150 mg/ml.
• a high concentration antibody formulation may present many challenges in formulation development, especially for liquid formulation.
• phase separation can occur through precipitation, gelation, and/or crystallization.
• the stability of an antibody can become problematic due to the formation of soluble and insoluble protein-protein aggregates.
• Highly concentrated antibody formulations are frequently highly viscous, which presents difficulties for processing, such as ultrafiltration and sterile filtration, and for injection of the dosage solution.
• the present disclosure provides liquid and lyophilized anti-PRLR antibody formulations with a wide range of anti-PRLR antibody concentrations, which are substantially isotonic and low viscosity and that contain substantially no salt other than an organic salt or an inorganic salt that is used to buffer the formulation.
• the anti-PRLR antibody formulations presented herein contain from about 0 mM to about 70 mM histidine; from about 50 ppm to about 300 ppm of a non-ionic surfactant such as, for example, polysorbate (Tween®) 80 and/or polysorbate (Tween®) 20; from about 34 mM to about 292 mM of a sugar or sugar alcohol such as, for example, mannitol, dextrose, glucose, trehalose, and/or sucrose; from about 0 mM to about 50 mM arginine; from about 0 mM to about 50 mM lysine; from about 0 mM to about 270 mM glycine or alanine; from about 0 mM to about 10 mM methionine; and from about 1 mg/ml to about 150 mg/ml of an anti-PRLR antibody, including an aPRLR-specific IgG2 monoclonal antibody (mAb) at
• Each of the presently disclosed antibody formulations contains substantially no salt other than an organic salt or an inorganic salt that is used to buffer the formulation. This permits the addition of alternative stabilizers to maintain the isosmoticity of the formulation (i.e., osmolality ranging from about 240 mmol/kg to about 380 mmol/kg), which thereby promotes a higher degree of patient compliance.
• the present disclosure provides anti-PRLR antibody formulations that stabilize the anti-PRLR antibody in a wide range of concentrations in liquid form or in lyophilized form at intended storage conditions.
• the formulations described herein include one or more pharmaceutically acceptable excipients or stabilizers, and are contained in buffered media at a suitable pH and are substantially isosmotic with physiological fluids.
• injection is one possible route of administration, including intramuscular, intravenous, intraperitoneal, and subcutaneous for injection.
• the high concentration, low viscosity, substantially isosmotic formulations disclosed herein are typically characterized by having a viscosity ranging from 1 to 8 mPa-S at 22 °C-23°C.
• osmolality refers to a measure of solute concentration, defined as the number of mmole of solute per kg of solution.
• a desired level of osmolality can be achieved by the addition of one or more stabilizer such as a sugar or a sugar alcohol including mannitol, dextrose, glucose, trehalose, and/or sucrose.
• the term “about” refers to +/- 10% of the unit value provided.
• the term “substantially” refers to the qualitative condition of exhibiting a total or approximate degree of a characteristic or property of interest.
• Non-ionic surfactants such as polysorbates, including polysorbate 20 and polysorbate 80; polyoxamers, including poloxamer 184 and 188; pluronic® polyols; and other ethylene/polypropylene block polymers, stabilize the anti-PRLR antibody during processing and storage by reducing interfacial interaction and prevent antibody from adsorption.
• Sugars and inorganic salts are commonly used as protein stabilizers; however, both sugars and inorganic salts are also effective tonicity agents. If a formulation requires a high concentration of one or more sugars to stabilize an anti- PRLR antibody, the inorganic salt concentration should be zero or kept very low in order to maintain the formulation's osmolality such that injection pain is reduced upon administration.
• salt refers to inorganic salts, which include sodium chloride (NaCl), sodium sulfate (Na 2 S0 4 ), sodium thiocyanate (NaSCN), magnesium chloride (MgCl), magnesium sulfate (MgS0 4 ), ammonium thiocyanate (NH 4 SCN), ammonium sulfate ((NH 4 ) 2 S0 4 ), ammonium chloride (NH 4 C1), calcium chloride (CaCl 2 ), calcium sulfate (CaSC>4), zinc chloride (ZnCl 2 ) and the like, or combinations thereof.
• antibody refers to a class of proteins that are generally known as immunoglobulins. Antibodies include full-length monoclonal antibodies (mAb), such as IgG2 monoclonal antibodies, which include immunoglobulin Fc regions. The term antibody also includes bispecific antibodies, diabodies, single-chain molecules, and antibody fragments such as Fab, F(ab') 2 , and Fv.
• mAb monoclonal antibodies
• IgG2 monoclonal antibodies which include immunoglobulin Fc regions.
• the term antibody also includes bispecific antibodies, diabodies, single-chain molecules, and antibody fragments such as Fab, F(ab') 2 , and Fv.
• Monoclonal antibodies also include "humanized monoclonal antibodies” wherein one or more complementarity determining region (CDR) from a heavy and/or light chain sequence from antibodies derived from one species replace one or more CDR from a heavy and/or light chain sequence from antibodies derived from a second species, and the second species may be human.
• CDR complementarity determining region
• the process of "humanization” is usually applied to monoclonal antibodies developed for administration to humans. See, e.g., Riechmann et al, Nature 332(6162):323-27 (1988) and Queen et al, Proc. Natl Acad. Sci. USA 86(24): 10029-33 (1989).
• PRLR antibody formulation refers to an amount of the formulation that provides therapeutic effect in an administration regimen.
• the high concentration anti-PRLR antibody formulations disclosed herein typically include an anti-PRLR antibody at a concentration ranging from about 1 mg/ml to about 150 mg/ml, or from about 2 mg/ml to about 120 mg/ml, or from about 5 mg/ml to about 100 mg/ml, or from about 7.5 mg/ml to about 60 mg/ml.
• concentration of anti- PRLR antibody within these formulations is about 2 mg/ml, or about 7.5 mg/ml, or about 20 mg/ml, or about 50 mg/ml, or about 60 mg/ml.
• Such formulations are typically administered in a volume of less than about 2 ml, or about 1.5 ml, or about 1 ml, or about 0.5 ml per injection site for subcutaneous injection.
• the anti-PRLR antibody formulation contains about 10 mM histidine, about 200 ppm polysorbate 20, about 88 mM sucrose, about 133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5.
• the anti-PRLR antibody formulation also contains from about 10 mM to about 50 mM arginine.
• the anti-PRLR antibody formulation contains about 10 mM histidine, about 75 ppm about polysorbate 80, about 234 mM sucrose, about 30 mM arginine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5.
• the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
• the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm about polysorbate 80, about 234 mM sucrose, about 20 mM arginine, about 150 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5.
• the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
• the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm about polysorbate 80, about 205 sucrose, about 20 mM arginine, about 1 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5.
• the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
• the anti-PRLR antibody formulation contains about 10 mM histidine, about 263 mM sucrose, about 80 ppm polysorbate 80, about 60 mg/mL anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5, such as pH 6.0.
• the present disclosure provides anti-PRLR mAb formulations, including anti-PRLR IgG2 mAb formulations, wherein the anit-PRLR mAb is soluble at high protein concentrations.
• the anti-PRLR mAb in the formulations disclosed herein remain soluble at concentrations of between about 1 mg/ml to about 150 mg/ml and remain stable under isosmotic storage conditions and exhibit reduced viscosity as compared to currently available antibody formulations.
• the antibody was reformatted into a human IgG2 of the IgG2m (n-) heavychain allotype lacking the C-terminal lysine.
• a potential deamidation site is present in CDR3 at amino acid position 98 of the light chain and was left unchanged in this antibody.
• the standard N-glycosylation site of IgG2 is present at N294 of the heavy chain.
• Anti-PRLR antibodies can prevent the onset or progression of endometriosis by blocking PRLR, thereby overcoming deficiencies in endometrial pathways.
• the wide protein concentration range, including high concentration anti-PRLR antibody formulations presented herein can be administrated to the patients via intravenous injection intramuscular injection or subcutaneous injection.
• an anti-PRLR antibody has a net positive charge.
• the repulsion of the positive charges on such an anti-PRLR antibody surface likely prevents protein-protein association between individual molecules and, thereby, significantly increases solubility.
• the anion (CI " ) of salt binds to the guanidinium group on arginine side-chains on an anti- PRLR antibody surface to neutralize the positive charges, which enhances protein- protein interactions and, hence, causes lower solubility and solution turbidity.
• the concentration of other stabilizers such as sucrose, can be increased to > 150 mM and ⁇ 300 mM without compromising osmolality.
• Frozen anti-PRLR antibody is thawed and formulated according to formulations presented in Table 2.
• the formulations are prepared and are sterile filtered with a 0.22 ⁇ filter and sterile filled in glass tubing vials and stoppered with rubber stoppers.

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