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WO2017100199A1 - Procédé d'utilisation d'il-27 en tant que biomarqueur prédictif de la réponse clinique à une thérapie à l'acétate de glatiramère - Google Patents

Procédé d'utilisation d'il-27 en tant que biomarqueur prédictif de la réponse clinique à une thérapie à l'acétate de glatiramère Download PDF

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Publication number
WO2017100199A1
WO2017100199A1 PCT/US2016/065175 US2016065175W WO2017100199A1 WO 2017100199 A1 WO2017100199 A1 WO 2017100199A1 US 2016065175 W US2016065175 W US 2016065175W WO 2017100199 A1 WO2017100199 A1 WO 2017100199A1
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Prior art keywords
glatiramer acetate
concentration
subject
multiple sclerosis
months
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English (en)
Inventor
Kouichi Ito
Suhayl Dhib-Jalbut
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Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5428—IL-10
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/285—Demyelinating diseases; Multipel sclerosis

Definitions

  • MS Multiple sclerosis
  • CNS central nervous system
  • RRMS relapsing-remitting
  • RRMS progressive course leading to neurologic deterioration and disability.
  • RRMS is the most common form of the disease (1) which is characterized by unpredictable acute episodes of neurological dysfunction (relapses), followed by variable recovery and periods of clinical stability.
  • SP secondary progressive
  • SP secondary progressive
  • PP primary progressive
  • MS is the most common cause of chronic neurological disability in young adults.
  • (3,4) Anderson et al . estimated that there were about 350, 000 physician-diagnosed patients with MS in the United States in 1990 (approx. 140 per 100,000 population) .
  • (5) It is estimated that about 2.5 million individuals are affected worldwide .
  • ( 6) In general, there has been a trend toward an increasing prevalence and incidence of MS worldwide, but the reasons for this trend are not fully understood. (5)
  • Glatiramer acetate is the active substance in Copaxone®, a marketed product indicated for reduction of the frequency of relapses in patients with RRMS . Its effectiveness in reducing relapse rate and disability accumulation in RR-MS is comparable to that of other available immunomodulating treatments .
  • Glatiramer acetate consists of the acetate salts of synthetic polypeptides containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L- tyrosine and L-lysine. The average molecular weight of glatiramer acetate is between 5,000 and 9,000 Daltons. At a daily standard dose of 20 mg, GA is generally well tolerated, however response to the drug is variable.
  • GA reduced relapse rates and progression of disability in patients with RR-MS.
  • the therapeutic effect of GA is supported by the results of magnetic resonance imaging (MRI) findings from various clinical centers (11), however there are no validated predictive biomarkers of response to GA treatment.
  • MRI magnetic resonance imaging
  • a possible initial mode of action of GA is associated with binding to MHC molecules and consequent competition with various myelin antigens for their presentation to T cells.
  • a further aspect of its mode of action is the potent induction of T helper 2 (Th2) type cells that presumably can migrate to the brain and lead to in situ bystander suppression .
  • Th2 T helper 2
  • Clinical experience with GA consists of information obtained from completed and ongoing clinical trials and from post-marketing experience.
  • the clinical program includes three double-blind, placebo- controlled studies in RRMS subjects treated with GA 20 mg/day. (18, 19, 20)
  • the relapse rate was reduced by 32% from 1.98 under placebo to 1.34 under GA 20 mg.
  • GA 20 mg has also demonstrated beneficial effects over placebo on MRI parameters relevant to RRMS.
  • a significant effect in median cumulative number of Gd-enhancing lesions over 9 months of treatment 11 lesions in the 20 mg group compared to 17 lesions under placebo) was demonstrated.
  • the clinical program with GA also includes one double-blind study in chronic-progressive MS subjects, (21) one double-blind placebo- controlled study in primary progressive patients, (22) one double-blind placebo-controlled study in CIS patients (23) and numerous open-label and compassionate use studies, mostly in RRMS .
  • the clinical use of GA has been extensively reviewed and published in the current literature. (24, 25,26, 27)
  • the present invention provides a method for treating a subject afflicted with multiple sclerosis with a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a glatiramer acetate responder by evaluating IL-27 concentration in the blood of the subject; and c) continuing the administration of the pharmaceutical composition if the subject is identified as a glatiramer acetate responder, or modifying treatment of the subject if the subject is not identified as a glatiramer acetate responder.
  • the present invention also provides a method for monitoring treatment of multiple sclerosis in a subject afflicted therewith, comprising: a) administering to the subject a therapeutic amount of a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier; and b) evaluating a change in IL-27 concentration in the blood of the subj ect .
  • the present invention also provides a method for determining clinical responsiveness to glatiramer acetate therapy in a subject afflicted with multiple sclerosis and receiving glatiramer acetate, the method comprising evaluating IL-27 concentration in the blood of the subject, to thereby determine clinical responsiveness to glatiramer acetate treatment .
  • IL-27 Differential production of IL-27 by Multiple Sclerosis (MS) and healthy donors (HP) peripheral blood mononuclear cells (PBMCs) in response to GA stimulation in vitro.
  • MS Multiple Sclerosis
  • HP healthy donors
  • PBMCs peripheral blood mononuclear cells
  • FIG. 1A-1C Production of IL-27 derived from the supernatants of human MS PBMC- samples which were cultured in the presence or absence of the indicated GA concentrations for 3 days.
  • PBMCs derived from different MS patients appear to segregate into groups of (Fig. 1A) efficient IL-27 producers, (Fig. IB) weak IL-27 producers, or (Fig.
  • IL-27 in PBMCs isolated from (Fig. 3A) efficient IL-27 producers, (Fig. 3B) weak IL-27 producers, and (Fig. 3C) IL-27 non- producers upon cultivation in the presence or absence of 50 ' ⁇ g/ml GA with/without ODN 684 or Pam3CSK4 at the indicated concentrations for 3 d. Data shown was pooled from three separate in vitro cell culture experiments carried out in triplicate wells. BD; below detection.
  • the present invention provides a method for treating a subject afflicted with multiple sclerosis with a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a glatiramer acetate responder by evaluating IL-27 concentration in the blood of the subject; and c) continuing the administration of the pharmaceutical composition if the subject is identified as a glatiramer acetate responder, or modifying treatment of the subject if the subject is not identified as a glatiramer acetate responder.
  • the present invention also provides a method for monitoring treatment of multiple sclerosis in a subject afflicted therewith, comprising: a) administering to the subject a therapeutic amount of a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier; and b) evaluating a change in IL-27 concentration in the blood of the subj ect .
  • the present invention also provides a method for determining clinical responsiveness to glatiramer acetate therapy in a subject afflicted with multiple sclerosis and receiving glatiramer acetate, the method comprising evaluating IL-27 concentration in the blood of the subject, to thereby determine clinical responsiveness to glatiramer acetate treatment .
  • the present invention also provides a method of predicting clinical responsiveness to glatiramer acetate therapy in a subject afflicted with multiple sclerosis and receiving glatiramer acetate, the method comprising evaluating IL-27 concentration in the blood of the subject, to thereby determine clinical responsiveness to glatiramer acetate treatment .
  • the multiple sclerosis is relapsing-remitting multiple sclerosis.
  • the IL-27 concentration is serum concentration.
  • the IL-27 concentration is PBMC supernatant concentration .
  • an increase in IL-27 concentration is associated with a subject being a responder to glatiramer acetate treatment.
  • the increase in IL-27 concentration is observed at 3 months after the first administration of glatiramer acetate.
  • the increase in IL-27 concentration is observed at 6 months after the first administration of glatiramer acetate.
  • the increase in IL-27 concentration is observed at 9 months after the first administration of glatiramer acetate.
  • the increase in IL-27 concentration is observed at 12 months after the first administration of glatiramer acetate.
  • the increase in IL-27 concentration is observed at 24 months after the first administration of glatiramer acetate.
  • the serum IL-27 concentration is greater than or equal to 1500 pg/ml.
  • the serum IL-27 concentration is greater than or equal to 1000 pg/ml, 1100 pg/ml, 1200 pg/ml, 1300 pg/ml, 1400 pg/ml, 1600 pg/ml, 1700 pg/ml, 1800 pg/ml, 1900 pg/ml, 2000 pg/ml, 2100 pg/ml, 2200 pg/ml, 2300 pg/ml, 2400 pg/ml or 2500 pg/ml .
  • the invention further comprises evaluating IL-10 concentration in the blood of the subject.
  • the IL-10 concentration is serum concentration.
  • the IL-10 concentration is PBMC supernatant concentration .
  • an increase in IL-10 concentration relative to baseline is associated with a subject being a responder to glatiramer acetate treatment.
  • the increase in IL-10 concentration is observed at 3 months after the first administration of glatiramer acetate.
  • the increase in IL-10 concentration is observed at 6 months after the first administration of glatiramer acetate.
  • the increase in IL-10 concentration is observed at 9 months after the first administration of glatiramer acetate.
  • the increase in IL-10 concentration is observed at 12 months after the first administration of glatiramer acetate.
  • the increase in IL-10 concentration is observed at 24 months after the first administration of glatiramer acetate.
  • the serum IL-10 concentration is greater than or equal to 45 pg/ml.
  • the serum IL-10 concentration is greater than or equal to 35 pg/ml, 40 pg/ml, 50 pg/ml, 55 pg/ml, 60 pg/ml, 65 pg/ml, 70 pg/ml or 75 pg/ml.
  • the invention further comprises evaluating the gene expression level of ⁇ 3 or p28 in the blood of the subject.
  • administering the pharmaceutical composition comprises administering to the human subject three subcutaneous injections of the pharmaceutical composition over a period of seven days with at least one day between every subcutaneous injection.
  • the pharmaceutical composition is a unit dose of a 1 ml aqueous solution comprising 20 mg of glatiramer acetate.
  • the pharmaceutical composition is a unit dose of a 1 ml aqueous solution comprising 40 mg of glatiramer acetate.
  • the human subject is a naive patient.
  • the human subject has been previously administered a multiple sclerosis drug other than glatiramer acetate.
  • the human subject is thereafter administered the pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier as monotherapy.
  • the human subject is thereafter administered a multiple sclerosis drug which is not glatiramer acetate .
  • the present invention also provides a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier for use in treating a human subject afflicted with multiple sclerosis, wherein the human subject has been administered a therapeutic amount of the pharmaceutical composition, and wherein the human subject is determined as a glatiramer acetate responder as identified by having an increase of IL-27 concentration in the blood of the subject.
  • the present invention also provides a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier for the manufacture of a medicament for use in treating a human subject afflicted with multiple sclerosis, wherein the human subject has been administered a therapeutic amount of the pharmaceutical composition, and wherein the human subject is determined as a glatiramer acetate responder as identified by having an increase of IL-27 concentration in the blood of the subject.
  • the present invention also provides a use of a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier for treating a human subject afflicted with multiple sclerosis, wherein the human subject has been administered a therapeutic amount of the pharmaceutical composition, and wherein the human subject is determined as a glatiramer acetate responder as identified by having an increase of IL-27 concentration in the blood of the subject.
  • MS MS
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS secondary progressive multiple sclerosis
  • Benign multiple sclerosis is a retrospective diagnosis which is characterized by 1-2 exacerbations with complete recovery, no lasting disability and no disease progression for 10-15 years after the initial onset. Benign multiple sclerosis may, however, progress into other forms of multiple sclerosis.
  • SPMS may evolve from RRMS. Patients afflicted with SPMS' have relapses, a diminishing degree of recovery during remissions, less frequent remissions and more pronounced neurological deficits than RRMS patients. Enlarged ventricles, which are markers for atrophy of the corpus callosum, midline center and spinal cord, are visible on MRI of patients with SPMS.
  • PPMS is characterized by a steady progression of increasing neurological deficits without distinct attacks or remissions. Cerebral lesions, diffuse spinal cord damage and evidence of axonal loss are evident on the MRI of patients with PPMS. PPMS has periods of acute exacerbations while proceeding along a course of increasing neurological deficits without remissions. Lesions are evident on MRI of patients suffering from PRMS . (28)
  • a clinically isolated syndrome is a single monosymptomatic attack compatible with MS, such as optic neuritis, brain stem symptoms, and partial myelitis.
  • Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis (CDMS) .
  • CDMS clinically definite multiple sclerosis
  • Multiple sclerosis may present with optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of coordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence) , bowel problems (including constipation and loss of bowel control ), impotence, diminished sexual arousal, loss of sensation, sensitivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning.
  • Relapsing Form of Multiple Sclerosis includes:
  • relapsing forms of multiple sclerosis include: Relapsing-remitting multiple sclerosis (RRMS) , characterized by unpredictable acute episodes of neurological dysfunction (relapses) , followed by variable recovery and periods of clinical stability;
  • RRMS Relapsing-remitting multiple sclerosis
  • SPMS Secondary Progressive MS
  • PRMS Primary progressive-relapsing multiple sclerosis
  • PRMS progressive-relapsing multiple sclerosis
  • a subject afflicted with multiple sclerosis includes a subject who has been clinically diagnosed to have multiple sclerosis or relapsing multiple sclerosis (RMS) , which includes relapsing- remitting multiple sclerosis (RRMS) and Secondary Progressive multiple sclerosis (SPMS), or is a subject presenting a clinically isolated syndrome (CIS) .
  • RMS relapsing multiple sclerosis
  • SPMS Secondary Progressive multiple sclerosis
  • CIS clinically isolated syndrome
  • Relapses are characterized by the occurrence of neurological dysfunction symptoms, appearing after a 30-day period of stability or improvement and lasting for more than 24 hours (no infection, no fever) . The number of relapses are analyzed using a logistic regression model controlling for treatment and age.
  • Relapse Rate is the number of confirmed relapses per unit time.
  • Annualized relapse rate is the mean value of the number of confirmed relapses per each patient multiplied by 365 and divided by the number of days on study drug per each patient.
  • the "Kurtzke Expanded Disability Status Scale (EDSS)" is a method of quantifying disability in multiple sclerosis.
  • the EDSS replaced the previous Disability Status Scales which used to bunch people with MS in the lower brackets.
  • the EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these.
  • the Functional Systems are: pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual & cerebral (according to www. mult- sclerosis . org/expandeddisabil itystatusscale) .
  • a “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.
  • therapeutic when referring to an amount of the compound refers to the quantity of the compound that is sufficient to yield a desired therapeutic response, which can be measured by an improvement of a symptom.
  • symptoms can include a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, time to confirmed disease progression, time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, visual function, fatigue, impaired mobility, cognitive impairment, brain volume, abnormalities observed in whole Brain MTR histogram, general health status, functional status, quality of life, and/or symptom severity on work.
  • modifying treatment includes stopping treatment with glatiramer acetate, stopping treatment of glatiramer acetate in favor of an alternative treatment, adding a further treatment to be used in conjunction with glatiramer acetate, changing the dose of glatiramer acetate, or any combination thereof.
  • PBMCs peripheral blood mononuclear cells
  • the "supernatant" at "3 months", “6 months”, “9 months”, “12 months” or “24 months” refer to supernatants collected from PBMCs purified from subject blood samples taken at 3, 6, 9, 12 or 24 months, respectively, and incubated in the presence of antigen i.e., glatiramer acetate, as described in the methods hereinbelow.
  • concentration observed at a certain month refers to a concentration in the supernatant of PBMC derived from the subject's blood at that month.
  • concentration may be measured in freshly isolated cells or in cryopreserved cells after thawing.
  • a subject at "baseline” is a subject prior to administration of the compound.
  • administering to the subject means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition.
  • the administration can be periodic administration. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.
  • Treating encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., Relapsing MS (RMS) , or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder.
  • Treating as applied to patients presenting CIS can mean delaying the onset of clinically definite multiple sclerosis (CDMS) , delaying the progression to CDMS, reducing the risk of conversion to CDMS, or reducing the frequency of relapse in a patient who experienced a first clinical episode consistent with multiple sclerosis and who has a high risk of developing CDMS.
  • CDMS clinically definite multiple sclerosis
  • “Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
  • a "symptom" associated with MS or RMS includes any clinical or laboratory manifestation associated with MS or RMS and is not limited to what the subject can feel or observe.
  • a "naive patient” is a subject that has not been treated with any multiple sclerosis drug.
  • a “multiple sclerosis drug” is a drug or an agent intended to treat clinically defined MS, CIS or symptoms of any of the above mentioned diseases.
  • “Multiple sclerosis drugs” may include but are not limited to antibodies, immunosuppressants, anti-inflammatory agents, immunomodulators , cytokines, cytotoxic agents and steroids and may include approved drugs, drugs in clinical trial, or alternative treatments, intended to treat clinically defined MS, CIS or any form of neurodegenerative or demyelinating diseases.
  • “Multiple sclerosis drugs” include but are not limited to Interferon and its derivatives (including BETASERON®, AVONEX® and REBIF®) , Mitoxantrone and Natalizumab. Agents approved or in-trial for the treatment of other autoimmune diseases, but used in a MS or CIS patient to treat MS or CIS are also defined as multiple sclerosis drugs.
  • glatiramer acetate or a glatiramer acetate-related peptide or polypeptide is intended to include any peptide or polypeptide, including a random copolymer, that cross-reacts functionally with myelin basic protein (MBP) and is able to compete with MBP on binding to the MHC class II in the antigen presentation .
  • MBP myelin basic protein
  • a copolymer for use as active agent in the present invention may be a random copolymer comprising a suitable quantity of a positively charged amino acid such as lysine (K) or arginine (R) , in combination with a negatively charged amino acid (preferably in a lesser quantity) such as glutamic acid (E) or aspartic acid (D) , optionally in combination with a non-charged neutral amino acid such as alanine (A) or glycine (G) , serving as a filler, and optionally with an amino acid adapted to confer on the copolymer immunogenic properties, such as an aromatic amino acid like tyrosine (Y) or tryptophan (W) .
  • a positively charged amino acid such as lysine (K) or arginine (R)
  • a negatively charged amino acid preferably in a lesser quantity
  • glutamic acid (E) or aspartic acid (D) optionally in combination with a non-charged neutral amino acid such as alanine
  • the copolymers for use in the present invention can be composed of L- or D-amino acids or mixtures thereof. As is known by those of skill in the art, L-amino acids occur in most natural proteins. However, D- amino acids are commercially available and can be substituted for some or all of the amino acids used to make the copolymers used in the present invention.
  • the present invention contemplates the use of copolymers containing both D- and L-amino acids, as well as copolymers consisting essentially of either L- or D-amino acids.
  • the active agent for use in the present invention comprises at least one random three- or four-amino acid copolymer comprising one amino acid selected from each of the four following groups: (a) lysine (K) and arginine (R) ; (b) glutamic acid (E) and aspartic acid (D) ; (c) alanine (A) and glycine (G) ; and (d) tyrosine (Y) and tryptophan ( ) .
  • the copolymer comprises a combination of the amino acids tyrosine, glutamic acid, alanine, and lysine, herein designated poly-YEAK, of net overall positive electrical charge, and is most preferably GA, of the following molar ratio of the amino acids: about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine, and about 0.34 lysine. It may be a low molecular weight or high molecular weight copolymer being a polypeptide from about 15 to about 100, preferably from about 40 to about 80, amino acids in length.
  • the copolymer has an average molecular weight of about 2,000- 40,000 Da, preferably of about 2,000-13,000 Da, more preferably of about 4,700-13,000 Da, most preferably of about 5,000-9,000 Da, and mostly preferred of about 6,000-8,000 Da.
  • Preferred molecular weight ranges and processes for making a preferred form of GA are described in U.S. Patent No. 5,800,808, the entire contents of which are hereby incorporated by reference in their entirety as if fully disclosed herein .
  • the active agent of the present invention is a GA-related polypeptide that is a random copolymer containing four different amino acids, each from a different one of the groups (a) to (d) , but excluding GA.
  • the activity exhibited by GA is expected to remain if one or more of the following substitutions is made in the amino acid composition of the copolymer: aspartic acid (D) for glutamic acid (E) , glycine (G) for alanine (A) , arginine (R) for lysine (K) , and tryptophan (W) for tyrosine (Y) .
  • the GA-related polypeptide of the invention may include any of those copolymers disclosed in WO 00/05250, the entire contents of which being hereby incorporated herein by reference as if fully disclosed herein, and other synthetic amino acid copolymers such as the random four-amino acid copolymers described by Fridkis-Hareli et al.
  • copolymers 14-, 35- and 50-mers containing the amino acids phenylalanine, glutamic acid, alanine and lysine (poly-FEAK) , or tyrosine, phenylalanine, alanine and lysine (poly-YFAK) , and any other similar copolymer to be discovered that can be considered a universal antigen similar to GA.
  • the GA-related polypeptide of the invention is a copolymer containing a combination of three different amino acids each from a different one of three groups of the groups (a) to (d) .
  • These copolymers are herein referred to as terpolymers .
  • the mole fraction of amino acids of the terpolymers is about what is preferred for GA.
  • the terpolymers for use in the present invention contain tyrosine (Y) , alanine (A) , and lysine (K) , hereinafter designated poly-YAK.
  • the average molar fraction of the amino acids in these terpolymers can vary.
  • tyrosine can be present in a mole fraction of about 0.005-0.250;
  • alanine can be present in a mole fraction of about 0.3-0.6;
  • lysine can be present in a mole fraction of about 0.1-0.5, but preferably the molar ratios of tyrosine, alanine and lysine are about 0.10 to about 0.54 to about 0.35.
  • the average molecular weight of poly-YAK is about 2,000-40,000 Da, preferably about 3,000-35,000 Da, more preferably about 5,000- 25,000 Da. It is possible to substitute arginine (R) for lysine (K), glycine (0) for alanine (A), and or tryptophan (W) for tyrosine (Y) .
  • the terpolymers for use in the present invention contain tyrosine (Y) , glutamic acid (E) , and lysine (K) , hereinafter designated poly-YEK.
  • the average mole fraction of the amino acids in these terpolymers can vary: glutamic acid can be present in a mole fraction of about 0.005-0.300, tyrosine can be present in a mole fraction of about 0.005-0.250, and lysine can be present in a mole fraction of about 0.3-0.7, but preferably the molar ratios of glutamic acid, tyrosine, and lysine are about 0.26 to about 0.16 to about 0.58.
  • the average molecular weight of poly-YEK is about 2,000-40,000 Da, preferably about 3,000-35,000 Da, more preferably about 5,000-25,000 Da. It is possible to substitute arginine (R) for lysine (K) , aspartic acid (D) for glutamic acid (E) , and/or tryptophan (W) for tyrosine (Y) .
  • the terpolymers for use in the present invention contain lysine (K) , glutamic acid (E) , and alanine (A) , hereinafter designated poly-KEA.
  • the average molar fraction of the amino acids in these polypeptides can also vary.
  • glutamic acid can be present in a mole fraction of about 0.005-0.300
  • lysine can be present in a mole fraction of about 0.2-0.7, but preferably the molar ratios of glutamic acid, alanine and lysine are about 0.15 to about 0.48 to about 0.36.
  • the average molecular weight of YEK is about 2,000-40,000 Da, preferably about 3,000-35,000 Da, more preferably about 5,000- 25,000 Da. It is possible to substitute arginine (R) for lysine (K) , aspartic acid (0) for glutamic acid (E) , and/or glycine (G) for alanine (A) .
  • the terpolymers for use in the present invention contain tyrosine (Y) , glutamic acid (E) , and alanine (A) , hereinafter designated poly-YEA.
  • the average molar fraction of the amino acids in these polypeptides can vary.
  • tyrosine can be present in a mole fraction of about 0.005-0.250
  • glutamic acid can be present in a mole fraction of about 0.005-0.300
  • alanine can be present in a mole fraction of about 0.005-0.800, but preferably the molar ratios of glutamic acid, alanine, and tyrosine are about 0.21 to about 0.65 to about 0.14.
  • the average molecular weight of poly-YEA is about 2,000-40,000 Da, preferably about 3,000-35,000 Da, and more preferably about 5,000-25,000 Da. It is possible to substitute tryptophan (W) for tyrosine (Y) , aspartic acid (D) for glutamic acid (E) , and/or glycine (G) for alanine (A) .
  • W tryptophan
  • Y tyrosine
  • D aspartic acid
  • E glutamic acid
  • G glycine
  • A alanine
  • the terpolymers can be made by any procedure available to one of skill in the art for example as described in the above-mentioned publications WO 01152878 and WO 01/93893.
  • polypeptides of fixed sequence can readily be prepared and tested for binding to the peptide-binding groove of the HLA-DR molecules as described in Fridkis-Hareli et al.(32) Examples of such peptides are those disclosed in WO 005249, the entire contents of which are hereby incorporated by reference as if fully disclosed herein.
  • "about” with regard to a stated number encompasses a range of +10 percent to -10 percent of the stated value.
  • about 100 mg/kg therefore includes the range 90-100 mg/kg and therefore also includes 90, 91, 92, 93, 94, 95, 96, 9 ' 7, 98, 99, 100, " lOl, 102, 103, 104, 105, 106, 107, 018, 109 and 110 mg/kg. Accordingly, about 100 mg/kg includes, in an embodiment, 100 mg/kg.
  • 0.2-5 mg/kg is a disclosure of 0.2 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.23 mg/kg etc. up to 0.3 mg/kg, 0.31 mg/kg, 0.32 mg/kg, 0.33 mg/kg etc. up to 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg etc. up to 5.0 mg/kg.
  • IL-27 is a heterodimeric cytokine belonging to the IL-6/IL-12 family, which is composed of the p28 and p40-related Epstein-barr virus-induced gene 3 (EBI3) subunits (Yoshida and Miyazaki, 2008) . So far, the main source of IL-27 appears to be APCs upon stimulation of the Toll-like receptor (TLR) signaling pathway through myeloid differentiation primary response gene(MYD)88 (Plan et al . , 2002; Wirtz et al .
  • TLR Toll-like receptor
  • a GA-R is a patient with no relapses and no evidence of disease progression as measured by EDSS at the end of treatment with GA.
  • a GA-NR is a patient with one or more relapses or with progression in the EDSS of at least 1 point sustained for 6 months.
  • Human PBMCs used in this study were isolated from the whole blood of HD (NBAH blood center, New Brunswick, NJ) and MS patients by Ficoll- Hypaque gradient as previously described ( Dhib-Jalbut et al . , 2013) . All cells were cultured with GA (Teva Pharmaceutical Industries Ltd., Israel) in the presence or absence of TLR ligands; Pam3CSK4 (TLR-2) and ODN 684 (TLR-9) (InvivoGen) for 3 days. Cytokine production of IL- 27 and IL-10 was evaluated by ELISA kits (R&D Systems) .
  • GRAPHPAD PRISM SOFTWARE was used throughout this study for statistical analyses. P-values for significant production of serum IL-27 and IL-10 amongst GA-treated patients enlisted in the study were calculated by Student's t-test. All p-values ⁇ 0.05 were considered statistically significant . Results
  • PBMCs peripheral blood mononuclear cells
  • IL-27 is composed of EBI3 and p28 subunits
  • the induction of the EBI3 and p28 subunits within the PBMCs of an efficient IL-27 producer and IL-27 non-producer MS patient, respectively was analyzed.
  • the induction of EBI3 gene expression was slightly up-regulated in the efficient IL-27 producer and IL-27 non-producer ( ⁇ 2.2-fold and -1.6- fold, respectively)
  • the induction of p28 gene expression was much greater in the efficient IL-27 producer ( ⁇ 5.9-fold) (Fig. 2A-2B) .
  • the level of p28 gene expression in the IL-27 non- producer was similar to the expression level of the EBI3 subunit 5-fold) (Fig. 2A-2B) . Therefore, GA can induce p28 gene more efficiently compared to EBI3 gene and efficient IL-27 producers are more likely to induce greater p28 gene expression in response to GA, while IL-27 non-producers may fail to up-regulate p28 gene expression after GA stimulation.
  • Augmentation of IL-27 production via GA stimulation in the presence of TLR stimuli depends on initial IL-27 production in response to GA
  • TLRs Signaling through TLRs can lead to inflammation associated with the activation of innate and adaptive immunity.
  • TLRs not only recognize pathogen-associated molecular patterns, but endogenous damage- associated molecular patterns which can be released into the host during inflammatory responses as well.
  • TLRs are also found up-regulated on both infiltrating and resident CNS cells in MS and EAE. (33)
  • MS PBMCs in the presence or absence of GA and increasing amounts of TLR9 agonist (ODN BW006) , or TLR2 agonist (Pam3CSK4) were cultured, and assessed IL-27 production.
  • IL-27 production upon stimulation of human MS and HD PBMCs with GA in vitro were identified.
  • GA stimulation could also augment the production of IL-27 from MS PBMCs cultured in the presence of TLR agonists.
  • IL-27 and IL-10 were also increased in the serum of GA-R in comparison to GA-NR. This indicates that IL-27 induction by GA may be one of the unidentified links between GA and its beneficial immunomodulatory effects on immune system in MS treatment.
  • future experiments are required to screen the GA-R and GA-NR by measuring the GA-mediated IL-27 production in PBMCs .
  • Fridkis-Hareli M Santambrogio L, Stern JN, Fugger L, Brosnan C, Strominger JL . Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. J Clin Invest 109: 1635-1643 (2002) . Fridkis-Hareli M, Neveu JM, Robinson RA, Lane WS, Gauthier L, Wucherpfennig KW, Sela M, Strominger JL . Binding motifs of copolymer 1 to multiple sclerosis-and rheumatoid arthritis- associated HLA-DR molecules . J Immunol 162 : 4697-4704 (1999).
  • IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10- producing Trl cells.
  • Glatiramer acetate mechanisms of action in multiple sclerosis. Autoimmun Rev 6, 469-475.
  • Fridkis-Hareli M., Teitelbaum, D., Gurevich, E., Pecht, I., Brautbar, C, Kwon, O.J., Brenner, T., Arnon, R. , Sela, M., 1994. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity. Proc Natl Acad Sci U S A 91, 4872-4876.

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Abstract

La présente invention concerne un procédé de traitement d'un sujet atteint d'une sclérose en plaques au moyen d'une composition pharmaceutique comprenant de l'acétate de glatiramère et un support pharmaceutiquement acceptable, comprenant les étapes suivantes : a) administrer une quantité thérapeutique de la composition pharmaceutique au sujet ; b) déterminer si le sujet est un sujet répondant à l'acétate de glatiramère en évaluant la concentration d'IL-27 dans le sang du sujet ; et c) poursuivre l'administration de la composition pharmaceutique si le sujet est identifié comme étant un sujet répondant à l'acétate de glatiramère, ou modifier le traitement du sujet si le sujet n'est pas identifié comme étant un sujet répondant à l'acétate de glatiramère.
PCT/US2016/065175 2015-12-07 2016-12-06 Procédé d'utilisation d'il-27 en tant que biomarqueur prédictif de la réponse clinique à une thérapie à l'acétate de glatiramère Ceased WO2017100199A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140322158A1 (en) * 2010-03-16 2014-10-30 Teva Pharmaceutical Industries, Ltd. Methods of treating a subject afflicted with an autoimmune disease using predictive biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis
WO2015112904A1 (fr) * 2014-01-24 2015-07-30 University Of Florida Research Foundation, Inc. Socs mimétiques pour le traitement de maladies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140322158A1 (en) * 2010-03-16 2014-10-30 Teva Pharmaceutical Industries, Ltd. Methods of treating a subject afflicted with an autoimmune disease using predictive biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis
WO2015112904A1 (fr) * 2014-01-24 2015-07-30 University Of Florida Research Foundation, Inc. Socs mimétiques pour le traitement de maladies

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