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WO2006108128A2 - Administration oculaire d'interferon tau - Google Patents

Administration oculaire d'interferon tau Download PDF

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Publication number
WO2006108128A2
WO2006108128A2 PCT/US2006/012980 US2006012980W WO2006108128A2 WO 2006108128 A2 WO2006108128 A2 WO 2006108128A2 US 2006012980 W US2006012980 W US 2006012980W WO 2006108128 A2 WO2006108128 A2 WO 2006108128A2
Authority
WO
WIPO (PCT)
Prior art keywords
interferon
tau
administering
eye
use according
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/US2006/012980
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English (en)
Other versions
WO2006108128A3 (fr
Inventor
Chih-Ping Liu
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.)
Pepgen Corp
Original Assignee
Pepgen Corp
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 Pepgen Corp filed Critical Pepgen Corp
Priority to CA002602850A priority Critical patent/CA2602850A1/fr
Priority to JP2008505560A priority patent/JP2008534690A/ja
Priority to AU2006232130A priority patent/AU2006232130A1/en
Publication of WO2006108128A2 publication Critical patent/WO2006108128A2/fr
Publication of WO2006108128A3 publication Critical patent/WO2006108128A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the subject matter described herein relates to ocular delivery of interferon- tau for treatment of eye disorders or systemic diseases.
  • Opthalmic preparations including solutions, suspensions, ointments, and ocular inserts, provide a convenient route of administering therapeutic drugs to human patients.
  • Drugs can be applied topically to the eye to exert a local effect in the eye or a systemic effect after absorption into the bloodstream via, for example, the blood vessels in the conjunctival mucosa.
  • Interferon-tau has been administered orally for treatment of systemic autoimmune conditions and viral infections (Soos, J. M. etal., J. Neuroimmunology, 75:43-50 (1997); Soos, J.M. et al., J. Immunology, 169(5): 2231-2235 (2002);
  • a treatment method comprising administering interferon-tau to the eye of a patient.
  • the patient is suffering from a disorder, systemic or localized ocular, that is responsive to interferon-tau.
  • interferon-tau is administered to the eye in the form of a solution, a suspension, or an ointment. These preparations can be formulated, in other embodiments, for sustained release.
  • Ocular devices are also contemplated, such as an ocular insert.
  • the interferon-tau has a certain degree of identity to the protein identified herein as SEQ ID NO:2.
  • the interferon-tau is formulated with histidine, for increased stability and/or solubility in aqueous formulations.
  • SEQ ID NO:1 corresponds to an amino acid sequence of mature ovine interferon- ⁇ (IFN ⁇ ; oTP-1 ; GenBank Accession No. Y00287; PID g1358).
  • SEQ ID NO:2 corresponds to an amino acid sequence of mature ovine IFNx, where the amino acid residues at positions 5 and 6 of the sequence are modified relative to the sequence of SEQ ID NO:1.
  • Interferon-tau refers to any one of a family of interferon proteins having at least one characteristic from each of the following two groups of characteristics: (i) (a) anti-luteolytic properties, (b) antiviral properties, (c) anti-cellular proliferation properties; and (ii) about 45 to 68% amino acid homology with ⁇ -interferons and greater than 70% amino acid homology to known IFN ⁇ sequences (e.g., Ott, et al., J. Interferon Res., VV.357 (1991 ); Helmer, et al., J. Reprod. Fert., 79:83 (1987); Imakawa, et al., MoI.
  • IFN ⁇ Interferon-tau
  • Amino acid homology can be determined using, for example, the LALIGN program with default parameters. This program is found in the FASTA version 1.7 suite of sequence comparison programs (Pearson and Lipman, PNAS, 85:2444 (1988); Pearson, Methods in Enzymology, 183:63 (1990); program available from William R. Pearson, Department of Biological Chemistry, Box 440, Jordan Hall, Charlottesville, VA).
  • IFN ⁇ sequences have been identified in various ruminant species, including but not limited to, cow (Bovine sp., HelmerS.D., J. Reprod. Fert., 79:83 (1987); Imakawa, K., MoI. Endocrinol., 119:532 (1988)), sheep (Ovine sp.), musk ox (Ovibos sp.), giraffe (Giraffa sp., GenBank Accession no. U55050), horse ⁇ Equus caballus), zebra ⁇ Eq ⁇ us burchelli, GenBank Accession no.
  • interferon-tau intends to encompass the interferon-tau protein from any ruminant species, exemplified by those recited above, that has at least one characteristic from each of the following two groups of characteristics listed above.
  • Ovine IFN ⁇ refers to a protein having the amino acid sequence as identified herein as SEQ ID NO:1, and to proteins having amino acid substitutions and alterations such as neutral amino acid substitutions that do not significantly affect the activity of the protein, such as the IFN ⁇ protein identified herein as SEQ ID NO:2. More generally, an ovine IFN ⁇ protein is one having about 80%, more preferably 90%, sequence homology to the sequence identified as SEQ ID NO:1. Sequence homology is determined, for example, by a strict amino acid comparison or using one of the many programs commercially available.
  • Treating a condition refers to administering a therapeutic substance effective to reduce the symptoms of the condition and/or lessen the severity of the condition.
  • a condition "responsive to interferon therapy” is one in which the existence, progression, or symptoms of the condition is altered upon administration of an interferon, in particular a type-l interferon, and more particularly, interferon-tau. More preferably, a condition responsive to interferon therapy is one where the existence, progression, or symptoms of the condition are alleviated by IFN ⁇ administered parenterally or orally.
  • a treatment method comprising administering IFN ⁇ to the eye of a human patient.
  • IFNx is a type I IFN first identified as a pregnancy recognition hormone in ruminants, such as sheep and cows (Bazer, F. VV. et al., Am. J. Reprod. Immunol. 26:19-22 (1991)).
  • the protein possesses antiviral and anti-proliferative properties, with considerably lower toxicity than other type I interferons (Pontzer, C 1 et al., Biochem. Biophys. Res.
  • ovine IFN ⁇ shares about 45-55% identity with IFN- ⁇ s from human, mouse, rat, and pig and 70% homology with bovine IFN- ⁇ ll, now referred to as IFN- ⁇ .
  • a cDNA of ovine IFN ⁇ and several cDNA sequences which may represent different isoforms have been reported in the literature (Imakawa, K. et al, Nature, 330:377-379, (1987); Stewart, H.J., et al, . MoI. Endocrinol.
  • the 172 amino acid sequence of ovine-IFN ⁇ is set forth, for example, in U.S. Patent No. 5,958,402, and its homologous bovine-IFN ⁇ sequence is described, for example, in Helmer et al., J. Reprod. Fert., 79:83-91 (1987) and Imakawa, K. et al., MoI. Endocrinol., 3:127 (1989).
  • the sequences of ovine-IFN ⁇ and bovine-IFN ⁇ from these references are hereby incorporated by reference.
  • An amino acid sequence of ovine IFN ⁇ is shown herein as SEQ ID NO:1.
  • a modified amino acid sequence of ovine IFN ⁇ is shown herein as SEQ ID NO:2.
  • IFN ⁇ is formulated in any pharmaceutically-acceptable vehicle for delivery to the eye.
  • the formulation is a solution or suspension or ointment that comprises lFN ⁇ .
  • the formulation may contain any physiologically compatible vehicle, as those skilled in the ophthalmic art can select using conventional criteria.
  • the vehicles may be selected from the known ophthalmic vehicles which include, but are not limited to, saline solution, water, mineral oil, petroleum jelly, polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, vegetable oils such as olive oil, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate, salts such as sodium chloride and potassium chloride, alcohols such as ethanol, n-propyl alcohol, and iso-propyl alcohol, and dimethyl sulfoxide. These vehicles can be used alone in various combinations.
  • the formulation can also be designed for sustained or controlled release in the eye.
  • formulations where the protein is entrapped or incorporated into particles, such as lipidic particles or polymeric particles, are contemplated.
  • the INF ⁇ formulation is administered topically as an ophthalmic drop (solution or suspension) or ophthalmic ointment containing an amount of the protein.
  • the preparation is administered in any quantity needed to provide the degree of treatment needed.
  • drops can be instilled into the eye multiple times throughout the day, for example, hourly, every 2-3 hours, or several times per day.
  • Delivery devices designed for ocular administration of drugs are also suitable for use in the treatment method.
  • exemplary devices include Ocusert ® and Lacrisert ® .
  • a reservoir of the active agent is prepared, the reservoir being a matrix, gel, or fluid.
  • the reservoir can be surrounded by additional polymer membrane layers, such as the ethylene-vinyl acetate membranes in the Ocusert ® device.
  • the device is placed in the conjunctival sac where the drug is released for a prolonged period of time.
  • the preparations described above can additionally include a preservative, a surfactant, a viscosity enhancer, a buffer.
  • the preparation contains with histidine, which acts to stabilize the tertiary structure of (FNx and to increase its solubility in aqueous formulations, as described in WO 2004/032863, which is incorporated by reference herein.
  • an ocular preparation as described above is administered for treatment of uveitis.
  • Uveitis is an inflammation of the uvea and is responsible for about 10% of the visual impairment in the U.S. Panuveitis refers to inflammationof the entire uveal (vascular) layer of the eye.
  • Posterior uveitis generally refers to chorioentinitis and anterior uveitis refers to iridocyclitis.
  • the inflammatory precuts, cells, fibrins, excess proteins, of these inflammations are commonly found in the fluid spaces of the eye, i.e., the anterior changer, posterior chamber, and vitreous space as well as infiltrating the tissue intimately involved in the inflammatory response.
  • Uveitis may occur following surgical or traumatic injury to the eye or as a component of another disorder, such as an autoimmune disease. Accordingly, the invention contemplates administering to a person suffering from uveitis an amount of IFN ⁇ delivered to the eye for treatment of the condition or relief of the symptoms.
  • an ocular preparation as described above is administered for treatment of Sjogren's syndrome.
  • Sjogren's syndrome is an autoimmune disease in which the body's immune system mistakenly attacks its own moisture producing glands.
  • the syndrome can occur alone or in combination with another connective tissue disorder, such as rheumatoid arthritis, systemic lupus, systemic sclerosis (scleroderma) or polymyositis/dermatomyositis.
  • Hallmark symptoms of Sjogren's syndrome are dry eyes and dry mouth, but it is a systemic disease, affecting many organs. Accordingly, it is contemplated to administer to a person suffering from Sjogren's syndrome an amount of IFN ⁇ delivered to the eye for treatment of the condition or relief of the symptoms, both locally in the eye and systemically.
  • an ocular preparation as described above is administered for treatment of a person at risk of an ocular tissue transplantation.
  • Corneal transplant also known as keratoplasty, involves replacing a patient's damaged cornea with a cornea from the eye of a human cadaver. Corneal transplant is done when vision is lost in an eye because the cornea has been damaged by disease or traumatic injury. Some of the disease conditions that might require corneal transplant include the bulging outward of the cornea
  • keratoconus a malfunction of the inner layer of the cornea (Fuchs' dystrophy), and painful swelling of the cornea (pseudophakic bullous keratopathy).
  • Some of these conditions cause cloudiness of the cornea; others alter its natural curvature, which can also reduce the quality of vision.
  • Injury to the cornea can occur because of chemical burns, mechanical trauma, or infection by viruses, bacteria, fungi, or protozoa.
  • Herpes virus is one of the more common infections leading to corneal transplant. Accordingly, it is contemplated to administer to a person having a cornea transplant an amount of IFN ⁇ delivered to the eye for prevention of tissue rejection. More generally, the invention contemplates administering IFN ⁇ to the eye in an amount to inhibit rejection of a tissue or organ transplant.
  • an ocular preparation as described above is administered for treatment of a systemic disorder that is responsive to IFN ⁇ .
  • Systemic disorders include autoimmune, inflammatory, viral infections, proliferative and hyperproliferative diseases, as well as immunologically-mediated diseases.
  • An ophthalmic preparation comprising INF ⁇ is prepared and delivered in an amount sufficient to treat the condition or ameliorate the symptoms associated with the condition.
  • the ocular iFN ⁇ preparation can be administered alone or in combination with another therapeutic agent, given by any route of administration.
  • Selection of a second agent is made by a primary caregiver and typically relates to the condition from which the patient suffers.
  • Sjogren's syndrome is often accompanied by another condition, such as rheumatoid arthritis.
  • IFN ⁇ is administered to the eye for local treatment of Sjogren's syndrome and a second agent, such as a pain reliever or a steroid, is administered parenterally or orally for treatment of the conditions associated with rheumatoid arthritis.
  • IFN ⁇ can be administered to the eye for treatment of a systemic autoimmune condition, such as multiple sclerosis, along with a second drug, such as azathioprine, cyclophosphamide, corticosteroids (prednisone, prednisolone, others), cyclosporine, mycophenolate mofetil, antithymocyte globulin, muromonab-CD3 monoclonal antibody, mercaptopurine, mitoxantrone, glatiramer acetate (Copaxone), interferon-beta (AvonexTM, BetaseronTM, RibifTM), daclizumab, methotrexate, sirolimus, tacrolimus, and others.
  • the second drug can be administered orally, parenterally, or topically. Selection of other second therapeutic agents for combination with IFN ⁇ for a variety of conditions are readily identified by trained medical personnel. III. Examples
  • mice Eight Balb/c-mice are obtained for use in a study to evaluate the local and systemic effects of interferon-tau administered to the eye.
  • the mice are housed in standard cages in one room under controlled environmental conditions. Animals have free access to food and water throughout the study. Animals are observed daily for signs of ill health and only healthy animals with no ocular abnormalities are used for experiments.
  • Interferon-tau (SEQ ID NO:2) is prepared according to well known techniques and the specific activity is measured in a standard cytopathic effect assay (see, e.g., US 2005-0142109).
  • the protein is formulated in water and NaCI to make an isotonic solution.
  • the solution is instilled three times daily into the conjunctival sac of the right eye of each mouse in drop form (10-100 ⁇ L) to provide a dose of between 0.001-10 ⁇ g of interferon-tau.
  • mice After treatment for various periods of time, mice are sacrificed. Blood and tissue samples are collected for analysis of immunological markers, including IL-10, IL-12, IFN-gamma, other pro-inflammatory cytokines, chemokines, cellular markers, and biological markers, such as 2'-5'-oligoadenylate synthetase (OAS), indolamine dioxygenase, and interferon response genes, such as type I receptors, interferon- response factor 1 , MxA protein, neopterine, JAK, stat proteins.
  • immunological markers including IL-10, IL-12, IFN-gamma, other pro-inflammatory cytokines, chemokines, cellular markers, and biological markers, such as 2'-5'-oligoadenylate synthetase (OAS), indolamine dioxygenase, and interferon response genes, such as type I receptors, interferon- response factor 1 , MxA protein, neopterine, JAK
  • Interferon-tau SEQ ID NO:2
  • SEQ ID NO:2 is formulated in water and NaCI to make an isotonic solution. The solution is instilled into the conjunctival sac of the right eye of each rabbits by multiple 50 ⁇ L instillations (5 times in 20 minutes).
  • Animals are assigned a clinical ocular safety grade for the conjunctiva, cornea and iris according to a modified Draize scale at 0, 1 , 2 and 3 hours after the last instillation.
  • the left eye is instilled with physiological saline and serves as a control.
  • Interferon-tau is formulated in saline and histidine buffer to instillation into both eyes.
  • One drop of approximately 40 microliters is administered to the patient every two hours during waking hours for five consecutive days.
  • the acute phase and flare-ups of uveitis are measured using methods well known in the art, including symptoms such as increased clouding of the cornea, appearance of precipitates and new synechiae.
  • Clinical signs of the remission of uveitis are measured using clinical parameters such as disappearance of corneal clouding, absence of vasodilation in the iris. A diminished amount of precipitates and synechiae indicate remission.
  • Effectiveness of interferon-tau is evaluated using a Dry Eye Questionnaire that includes categorical scales to measure the prevalence, frequency, diurnal intensity, and intrusiveness of common ocular surface symptoms, including discomfort, dryness, visual changes, soreness and irritation, grittiness and scratchiness, burning and stinging, foreign body sensation, light sensitivity, and itching.
  • a Schirmer test for tear production is used to evaluate increase in tear production in treated patients.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des méthodes permettant de traiter les affections oculaires et les maladies systémiques en administrant de l'interféron tau à l'oeil.
PCT/US2006/012980 2005-04-05 2006-04-05 Administration oculaire d'interferon tau Ceased WO2006108128A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002602850A CA2602850A1 (fr) 2005-04-05 2006-04-05 Administration oculaire d'interferon tau
JP2008505560A JP2008534690A (ja) 2005-04-05 2006-04-05 インターフェロン−タウの眼内送達
AU2006232130A AU2006232130A1 (en) 2005-04-05 2006-04-05 Ocular delivery of interferon-tau

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US66868505P 2005-04-05 2005-04-05
US60/668,685 2005-04-05

Publications (2)

Publication Number Publication Date
WO2006108128A2 true WO2006108128A2 (fr) 2006-10-12
WO2006108128A3 WO2006108128A3 (fr) 2007-03-29

Family

ID=37074105

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/012980 Ceased WO2006108128A2 (fr) 2005-04-05 2006-04-05 Administration oculaire d'interferon tau

Country Status (4)

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JP (1) JP2008534690A (fr)
AU (1) AU2006232130A1 (fr)
CA (1) CA2602850A1 (fr)
WO (1) WO2006108128A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6372206B1 (en) * 1989-03-02 2002-04-16 University Of Florida Orally-administered interferon-TAU compositions and methods

Also Published As

Publication number Publication date
JP2008534690A (ja) 2008-08-28
CA2602850A1 (fr) 2006-10-12
WO2006108128A3 (fr) 2007-03-29
AU2006232130A1 (en) 2006-10-12

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