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WO2016189491A1 - Nouvelle formulation - Google Patents

Nouvelle formulation Download PDF

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Publication number
WO2016189491A1
WO2016189491A1 PCT/IB2016/053093 IB2016053093W WO2016189491A1 WO 2016189491 A1 WO2016189491 A1 WO 2016189491A1 IB 2016053093 W IB2016053093 W IB 2016053093W WO 2016189491 A1 WO2016189491 A1 WO 2016189491A1
Authority
WO
WIPO (PCT)
Prior art keywords
amyloid
formulation
antibody
amyloid antibody
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2016/053093
Other languages
English (en)
Inventor
Ulla Tove Lashmar
Ahmed YASIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline Intellectual Property Development Ltd
Original Assignee
GlaxoSmithKline Intellectual Property Development Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GlaxoSmithKline Intellectual Property Development Ltd filed Critical GlaxoSmithKline Intellectual Property Development Ltd
Publication of WO2016189491A1 publication Critical patent/WO2016189491A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention relates to an antibody formulation for treating diseases or disorders affecting the eye or optic nerve characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits, particularly age related macular degeneration and glaucoma type diseases and ⁇ -amyloid-dependent cataract formation, with antigen binding proteins that bind ⁇ -amyloid peptide and in particular human ⁇ -amyloid peptide.
  • diseases or disorders affecting the eye or optic nerve characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits, particularly age related macular degeneration and glaucoma type diseases and ⁇ -amyloid-dependent cataract formation
  • antigen binding proteins that bind ⁇ -amyloid peptide and in particular human ⁇ -amyloid peptide.
  • ⁇ -amyloid ⁇ -amyloid
  • GA geographic atrophy
  • AD Alzheimer's disease
  • ⁇ is a common therapeutic target and an anti- ⁇ antibody is believed to act by a postulated 'peripheral sink' mode of action resulting in an overall shift of ⁇ from the brain or eye into the plasma compartment. This shift, in turn, may translate into arrest or delay of the cognitive decline in AD patients, slowing of the progression of GA and loss of vision in AMD patients, and possibly even the slowing the transition to both GA and neovascular AMD from earlier stages of AMD.
  • WO 2009040336 discloses anti ⁇ -amyloid antibodies which are useful in the treatment of disease or disorder affecting the eye or optic nerve characterized by ⁇ -amyloid levels or ⁇ -amyloid deposits, more in particular AMD (including geographic atrophy), glaucoma or ⁇ -amyloid dependent cataract formation.
  • the pharmaceutical use of antibodies has increased over the past years. In many instances such antibodies are injected via the intravenous (IV) route. Unfortunately the amount of antibody that can be injected via the intravenous route is limited by the physico-chemical properties of the antibody, in particularly by its solubility and stability in a suitable liquid formulation and by the volume of the infusion fluid. Alternative administration pathways are subcutaneous or intramuscular injection.
  • the patient can be trained to perform the subcutaneous injection by himself.
  • Such self-administration is particularly useful during maintenance dosing because no hospital care is needed (reduced medical resource utilization).
  • injections via the subcutaneous route are limited to approximately 1.2 ml.
  • several unit dose formulations can be injected at multiple sites of the body surface.
  • the present invention generally relates to a high concentration formulation for delivering an anti-P-amyloid antibody for treating a human patient afflicted with a disease or disorder affecting the eye or optic nerve characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, in particular AMD (age-related macular degeneration, (including geographic atrophy), glaucoma or ⁇ -amyloid dependent cataract formation.
  • a disease or disorder affecting the eye or optic nerve characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, in particular AMD (age-related macular degeneration, (including geographic atrophy), glaucoma or ⁇ -amyloid dependent cataract formation.
  • AMD age-related macular degeneration, (including geographic atrophy)
  • glaucoma glaucoma or ⁇ -amyloid dependent cataract formation.
  • the formulation of the present invention discussed below achieves a high degree of thermal and shear stability and is particularly suited for long term storage for intramuscular and subcutaneous and intra-muscular delivery,
  • the invention relates to an anti-P-amyloid antibody formulation comprising a therapeutically effective amount of an anti-P-amyloid antibody, wherein the formulation further comprises 10 to 100 mM sodium acetate, 25 to 100 mM sodium chloride, 0.5 to 5% arginine free base, 0.02 to 0.2 mM EDTA, 0.01 to 0.2 % polysorbate 80 and adjusted to pH between 5.0 and 7.0 (preferably between 5.0 and 6.0, more preferably between 5.3 to 5.7, and even more preferably 5.5).
  • the invention relates to an anti-P-amyloid antibody formulation
  • an anti-P-amyloid antibody formulation comprising an anti-P-amyloid antibody in the concentration range of 20- 300 mg/mL (for example, 50mg/mL, lOOmg/mL, and 150mg/mL), wherein the formulation further comprises 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, 0.02% polysorbate 80, and adjusted to pH 5.5.
  • the invention relates to an anti- ⁇ -amyloid antibody formulation wherein the anti-P-amyloid antibody is present in an amount of about 50 mg/mL, lOOmg/mL, 150mg/mL, 20-300 mg/mL, 50-300 mg/mL, 100-300 mg/mL, 150-300 mg/mL, 200-300 mg/mL, or 250-300 mg/mL.
  • the invention relates to an anti-P-amyloid antibody formulation wherein sodium acetate is present in an amount of about 50mM, 40mM, 45mM, 55mM, or 60mM.
  • the sodium acetate may be present in an amount of 10 to 100 mM, 20 to 100 mM, 30 to 100 mM, 40 to 100 mM, 50 to 100 mM, 60 to 100 mM, 70 to 100 mM, 25 to 80 mM, or 30 to 70 mM.
  • the invention relates to an anti- ⁇ -amyloid antibody formulation wherein acetic acid is present (about 100 mM acetic acid) to adjust the formulation to about pH 5.5.
  • the pH may be adjusted to pH 5.0, 5.5, 6.0, 6.5 or 7.0.
  • NaOH or HC1 is used to adjust the pH to 5.0, 5.5, 6.0, 6.5 or 7.0.
  • the invention relates to an anti- ⁇ -amyloid antibody formulation wherein sodium chloride is present in an amount of about 51mM, 45mM, 46mM, 47mM, 48mM, 49mM, 50mM, 52mM, 53mM, 54mM, 55mM.
  • the sodium chloride may be present in an amount of 25 to 100 mM, 35 to 90 mM, 45 to 80 mM, 25 to 70 mM, or 45 to 70 mM.
  • the invention relates to an anti-P-amyloid antibody formulation wherein arginine free base is present in an amount of about 1%, 0.7%, 1.3%, or 2.0%).
  • the arginine free base may be between 0.5 and 5.0%, 0.5 to 2.0%, 0.5 to 2.5%, 0.5 to 3.0%, 0.5 to 3.5%, 0.5 to 4.0%, or 0.5 to 4.5%.
  • the invention relates to an anti-P-amyloid antibody formulation wherein EDTA is present in an amount of about 0.05 mM, 0.03 mM, 0.04 mM, or 0.06 mM.
  • the EDTA may be present in an amount of 0.02 mM - 0.2 mM, 0.02 mM - 0.1 mM, 0.02 mM - 0.15 mM, 0.04 mM - 0.1 mM, 0.03 mM - 0.15 mM, or 0.03 mM - 0.2 mM.
  • the invention relates to an anti-P-amyloid antibody formulation wherein polysorbate 80 is present in an amount of about 0.02%, 0.015%), or 0.025%).
  • the polysorbate 80 may be present in an amount of 0.01 - 0.2%, 0.01 - 0.15%, 0.02 - 0.2%, 0.02 - 0.15%, 0.01 - 0.25%, or 0.01 - 0.05%.
  • the invention relates to a method of treating a human patient afflicted with a disease or disorder affecting the eye or optic nerve
  • an anti-P-amyloid antibody formulation comprising a therapeutically effective amount of an anti-P-amyloid antibody, wherein the formulation further comprises 10 to 100 mM sodium acetate, 25 to 100 mM sodium chloride, 0.5 to 5% arginine free base, 0.02 to 0.2 mM EDTA, 0.01 to 0.2 % polysorbate 80 and adjusted to pH 5.0 to 7.0 and wherein the antibody formulation is administered orally, parenterally, intranasally, vaginally, rectally, lingually, sublingually, bucally, transdermally, intravenously, or subcutaneously to a mammal.
  • the invention relates to a method of treating a human patient afflicted with a disease or disorder affecting the eye or optic nerve
  • the present invention relates to a pharmaceutical formulation according to any above embodiments for use in therapy.
  • the present invention relates to a pharmaceutical formulation according to any above embodiments for the treatment of a disease or disorder amenable to treatment with an anti-P-amyloid antibody.
  • the present invention relates to a pharmaceutical formulation according to any above embodiments for use in the treatment of disease or disorder effecting the eye or optic nerve characterized by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits.
  • the disease or disorder above is age-related macular degeneration (AMD), geographic atrophy, glaucoma or ⁇ -amyloid dependent cataract formation.
  • AMD age-related macular degeneration
  • the present invention relates to the use of the
  • the use of the pharmaceutical formulation above in which the disease or disorder is age-related macular degeneration (AMD), geographic atrophy, glaucoma or ⁇ -amyloid dependent cataract formation.
  • AMD age-related macular degeneration
  • an anti-P-amyloid antibody of the invention refers to an antibody having a variable heavy and variable light region comprising the following CDRs:
  • CDRL1 RVSQSLLHSNGYTYLH (SEQ ID No:4)
  • CDRL2 KVSNRFS (SEQ ID No:5)
  • CDRL3 SQTRHVPYT (SEQ ID No:6)
  • the anti- ⁇ -amyloid antibody of the present invention refers to an antibody with a heavy variable region and light a variable region of SEQ ID NOs: 7 and 8, respectively.
  • the anti-P-amyloid antibody of the present invention refers to an antibody having heavy and light chains of SEQ ID NOs: 9 and 10 respectively, which is hereinbelow referred to as Antibody A.
  • the optimal embodiment of this invention was determined after significant screening studies and is a formula containing 50mg/mL of Antibody A in a solution containing 50mM sodium acetate, 0.02% polysorbate 80, 1%> arginine, 51mM sodium chloride, at pH 5.5.
  • One such screening study involved subjecting Antibody A to various ranges of pH while otherwise maintaining a constant buffer formulation.
  • the pH range investigated during this study was from pH 4.5 to pH 8.5 at 0.5 pH unit intervals.
  • Assays such as ELISA, RP-HPLC, and SEC-HPLC were used to determine the stability profile of the samples.
  • results from the pH investigation show that all assays agreed that the stability of Antibody A at 50°C is poor at pH 4.5, pH 8.0 and pH 8.5.
  • the ELISA results indicated that the highest activity was maintained following storage at 50°C for 3 weeks at pH ranging from 5.0 to 6.0.
  • the ELISA data also indicate that Antibody A has a poor thermal stability.
  • the RP-HPLC results suggested that the stability of Antibody A was highest in solutions with a pH ranging from pH 5.5 to 6.0.
  • LMWF low molecular weight fractions
  • Thermal stability of various formulation was investigated by the use of DSC over a range of pH values from pH 4.5 to pH 8.5 at 0.5 pH unit intervals. Table 5 lists the average thermal events for each sample and Figure 1 shows representative results. All the data suggest that the thermal stability for Antibody A is good irrespective of pH. Onset of denaturation ranged from 60.4°C to 72.0°C and precipitation (peak top) from approximately 70.4°C to 81.7°C. This event is further illustrated in Figure 1.
  • Antibody A was diluted to lmg/ml and lOmg/ml with acetate buffer pH 5.5 and spiked with
  • polysorbate 80 to achieve a concentration of 0.0%, 0.02% or 0.1% (w/v) in the samples for testing.
  • a 2mL sample of each solution was filtered through a 0.2 ⁇ filter and added to a luminescence cuvette with a stirring flea.
  • the cuvette was placed in a Perkin Elmer LS 50B fluorimeter thermostatted to 20°C and with stirring on high speed.
  • a measure of the quantity of visible particulates in the stirred cuvette was obtained from luminescence measurements with the excitation and emission wavelength set to 400nm. Analysis of the stirred sample was carried out every 30 minutes. Each study was continued for 360 minutes.
  • the luminescence with time for solutions with Antibody A concentration of l .Omg/ml with and without Polysorbate 80 is shown in Figure 2.
  • EDTA ethylenediaminetetraacetic acid

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Mycology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations contenant des anticorps dirigés contre le β-amyloïde pour le traitement de maladies ou de troubles affectant l'oeil ou le nerf optique caractérisés par des taux de β-amyloïde élevés ou des dépôts de β-amyloïde, tels que, notamment, la dégénérescence maculaire liée à l'âge (y compris l'atrophie géographique) ainsi que les maladies de type glaucome et la formation de cataracte dépendante du β-amyloïde, à l'aide de protéines de liaison à l'antigène se liant au peptide β-amyloïde, et notamment au peptide β-amyloïde humain.
PCT/IB2016/053093 2015-05-28 2016-05-26 Nouvelle formulation Ceased WO2016189491A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562167437P 2015-05-28 2015-05-28
US62/167,437 2015-05-28

Publications (1)

Publication Number Publication Date
WO2016189491A1 true WO2016189491A1 (fr) 2016-12-01

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ID=56137470

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/053093 Ceased WO2016189491A1 (fr) 2015-05-28 2016-05-26 Nouvelle formulation

Country Status (1)

Country Link
WO (1) WO2016189491A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022056484A1 (fr) * 2020-09-14 2022-03-17 Caelum Biosciences Méthode de traitement de l'amylose

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009406A1 (fr) * 2007-07-06 2009-01-15 Smithkline Beecham Corporation Formulations d'anticorps
WO2009009407A1 (fr) * 2007-07-06 2009-01-15 Smithkline Beecham Corporation Formulations d'anticorps
WO2009040336A1 (fr) 2007-09-25 2009-04-02 Glaxo Group Limited Protéines de liaison aux antigènes
WO2013011076A2 (fr) * 2011-07-19 2013-01-24 Glaxo Group Limited Protéines de liaison à un antigène ayant une liaison accrue à fcrn
JP2014062100A (ja) * 2013-11-05 2014-04-10 Glaxosmithkline Llc 抗体処方

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009406A1 (fr) * 2007-07-06 2009-01-15 Smithkline Beecham Corporation Formulations d'anticorps
WO2009009407A1 (fr) * 2007-07-06 2009-01-15 Smithkline Beecham Corporation Formulations d'anticorps
WO2009040336A1 (fr) 2007-09-25 2009-04-02 Glaxo Group Limited Protéines de liaison aux antigènes
WO2013011076A2 (fr) * 2011-07-19 2013-01-24 Glaxo Group Limited Protéines de liaison à un antigène ayant une liaison accrue à fcrn
JP2014062100A (ja) * 2013-11-05 2014-04-10 Glaxosmithkline Llc 抗体処方

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022056484A1 (fr) * 2020-09-14 2022-03-17 Caelum Biosciences Méthode de traitement de l'amylose

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